Summary Basis of Decision for Trajenta ™

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
TrajentaTM

Linagliptin, 5 mg, Tablet, Oral

Boehringer Ingelheim Canada Ltd.

Submission control no: 140881

Date issued: 2011-12-23

Foreword

Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

1 Product and submission information

Brand name:

TrajentaTM

Manufacturer/sponsor:

Boehringer Ingelheim Canada Ltd.

Medicinal ingredient:

Linagliptin

International non-proprietary Name:

Linagliptin

Strength:

5 mg

Dosage form:

Tablet

Route of administration:

Oral

Drug identification number(DIN):

  • 02370921

Therapeutic Classification:

Antihyperglycaemic agent, Dipeptidyl peptidase-4 (DPP-4) inhibitor, Incretin enhancer

Non-medicinal ingredients:

Tablet core:
Mannitol, pregelatinised starch, maize starch, copovidone, and magnesium stearate

Film-coating:
Hypromellose, titanium dioxide, talc, macrogol, and iron oxide red

Submission type and control no:

New Drug Submission,
Control Number: 140881

Date of Submission:

2010-08-17

Date of authorization:

2011-07-28
2 Notice of decision

On July 28, 2011, Health Canada issued a Notice of Compliance to Boehringer Ingelheim (Canada) Ltd. for the drug product, Trajenta™.

Trajenta™ contains the medicinal ingredient linagliptin which is an antihyperglycaemic agent. Trajenta™ is a potent, reversible and selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme which is involved in the inactivation of the incretin hormones. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. By enhancing active incretin levels, linagliptin increases insulin secretion and lowers glucagon levels in a glucose-dependent manner, thus resulting in an overall improvement of glucose homoeostasis.

Trajenta™ is indicated in adult patients with type 2 diabetes mellitus (T2DM) to improve glycaemic control.

Monotherapy

  • In conjunction with diet and exercise in patients for whom metformin is inappropriate due to contraindications or intolerance.

Combination Therapy

  • In combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
  • In combination with a sulfonylurea when diet and exercise plus a sulfonylurea alone do not provide adequate glycaemic control.
  • In combination with metformin and a sulfonylurea when diet and exercise plus metformin and a sulfonylurea do not provide adequate glycaemic control.

The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Trajenta™ were primarily based on six multicentre, randomized, double-blind studies, of which four were placebo-controlled, one was placebo-controlled followed by an active control and one was active-controlled. Of these six studies, three were of a 24-week duration, two were of an 18-week duration and one was of a 52-week duration. A total of 4,294 patients were enrolled and randomized within these studies. Results from these studies showed that treatment with Trajenta™ either as a monotherapy, or as an add-on combination therapy with metformin, a sulfonylurea, or both, resulted in statistically significant reductions of haemoglobin A1c (HbA1c) at study completion from the baseline HbA1c compared with patients receiving a placebo as a monotherapy, or as added to metformin, and/or a sulfonylurea.

Trajenta™ (5 mg, linagliptin) is presented in a tablet form. The recommended dose of Trajenta™ is 5 mg once daily. Trajenta™ can be taken with or without food. Dosing guidelines are available in the Product Monograph.

Trajenta™ is contraindicated for patients who are hypersensitive to Trajenta™ or to any ingredient in the formulation. Trajenta™ should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Trajenta™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Trajenta™ are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Trajenta™ is favourable for the indications stated above.

3 Scientific and Regulatory Basis for Decision

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)
General Information

Linagliptin, the medicinal ingredient of Trajenta™, is an inhibitor of DPP-4 activity for the treatment of type 2 diabetes mellitus. Linagliptin acts as an antihyperglycaemic agent, as well as an incretin enhancer. Linagliptin binds to DPP-4 in a reversible manner and thus leads to an increase and a prolongation of active incretin levels. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homoeostasis.

Manufacturing Process and Process Controls

The manufacturing process is considered to be adequately controlled within justified limits.

In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.

Characterization

The structure of linagliptin has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.

The impurities that were reported and characterized were found to be either within International Conference of Harmonisation (ICH) established limits or were qualified in toxicological studies and appropriate specifications were set.

Control of Drug Substance

The drug substance specifications and analytical methods used for quality control of linagliptin are considered acceptable.

Validation reports are considered satisfactory for all analytical procedures used for
in-process and release testing of the drug substance.

Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.

The proposed packaging components are considered acceptable.

Stability

Based on the long-term, accelerated, and stress stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.

3.1.2 Drug Product
Description and Composition

Trajenta™ tablets contain 5 mg of linagliptin. The tablets are light red, round, biconvex, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol and the other side is debossed with "D5". Trajenta™ is available in blister packs of 30 and 90 tablets.

The non-medicinal ingredients include: mannitol; pregelatinised starch; maize starch; copovidone; and magnesium stearate. The film-coating contains hypromellose, titanium dioxide, talc, macrogol and iron oxide red.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of linagliptin with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable.

Manufacturing Process and Process Controls

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Trajenta™ is tested to verify that its identity, appearance, content uniformity, assay, loss on drying, dissolution, and levels of degradation products are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.

Validation reports submitted for all analytical procedures used for release testing of the drug product are considered satisfactory.

Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.

Stability

Based on the data submitted, the proposed shelf-life at 15-30°C for Trajenta™ in the proposed blister packaging is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.

3.1.3 Facilities and Equipment

All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.

All sites are compliant with Good Manufacturing Practices.

3.1.4 Adventitious Agents Safety Evaluation

Not applicable. The excipients used in the drug product formulation are not from animal or human origin.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Trajenta™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-Clinical Basis for Decision

3.2.1 Pharmacodynamics

Linagliptin is a DPP-4 inhibitor developed as a treatment for the improvement of glycaemic control in type II diabetes. Inhibition of DPP-4 results in the prolongation of half-lives of short lived incretins and neuropeptides involved in the stimulation of insulin secretion in ß-cells. Linagliptin was shown to be a potent, reversible inhibitor of DPP-4 in vitro with the half maximal inhibitory concentration (IC50) ranging from 0.18-10.4 nM. Linagliptin showed a high degree of specificity for DPP-4 compared to other proteases, enzymes, receptors, and transporters. Oral treatment of rats, mice, dogs, and monkeys at 1 mg/kg resulted in the inhibition of plasma DPP-4 activity lasting for up to 24 hours supporting once a day dosing. The pharmacokinetic profile also supports once a day dosing.

3.2.2 Pharmacokinetics
Absorption

The oral bioavailability of linagliptin was approximately 50% in all species tested. The drug exposure parameters, area under the curve (AUC) and maximum plasma concentration (Cmax), increased more than proportionally with the dose suggesting non-linear mechanisms in the oral pharmacokinetics of linagliptin.

Distribution

Linagliptin had a large volume of distribution, as well as a long mean residence time and terminal half-life. The highest tissue concentrations and retention times of
linagliptin-related radioactivity were observed in the liver and kidney. Linagliptin crossed the blood placenta barrier in rats and rabbits, and was excreted with milk in lactating rats.

Plasma protein binding in multiple species (mice, rats, rabbits, dogs, and monkeys) ranged from approximately 70-99% with a marked concentration dependency.

Metabolism

Linagliptin was metabolized by the cytochrome P450 (CYP) isoenzyme CYP3A4 in humans and rats, first to a short-lived intermediate and then reduced to the metabolite CD 1790. In humans, CD 1790 was the only circulating metabolite with a systemic exposure in human plasma of >10% of the parent compound systemic exposure. It was also a metabolite in rats, mice, rabbits, and monkeys. In addition to CD 1790, other minor metabolites were observed and the metabolite profiles across the species did not differ substantially.

Linagliptin was a competitive, weak to moderate mechanism-based (irreversible) inhibitor of CYP3A4 and a substrate of P-glycoprotein (P-gp).

Excretion

The major elimination route for linagliptin and its metabolites was by the bile, and therefore the faeces. Linagliptin renal excretion was negligible after oral dosing of 1 mg/kg in the animals. However, renal excretion was dose-dependent and accounted for up to 20-30% of the dose at the higher doses.

3.2.3 Toxicology
Single-Dose Toxicity

The acute oral toxicity of linagliptin was low in rats and mice. The minimum lethal dose after a single dose was 1,000 mg/kg in rats and mice.

A single intravenous (IV) dose of 60 mg/kg was tolerated in rats and mice with no clinical signs or mortality.

Repeat-Dose Toxicity

Results of the toxicology studies show that linagliptin was well-tolerated in all species tested. Repeat oral dosing was associated with lethality/moribund euthanasia at ≥600 mg/kg in rats (>3,000 times the human clinical exposure), ≥600 mg/kg in mice (>3,000 times the human clinical exposure), 150 mg/kg in dogs (>1,500 times the human clinical exposure), and in one monkey at 100 mg/kg (>750 times the human clinical exposure). The causes of death were kidney and/or stomach toxicity in the rats and mice, and pseudoallergic reactions in the dogs. The cause of death was not determined in the monkey.

In mice, overt kidney toxicity was evident at 600 mg/kg. In rats, increases in plasma creatinine and urea, as well as increases in kidney weight and/or microscopic tubular damage were reported at doses of ≥100 mg/kg. In the monkey, there were no microscopic changes in the kidney; however, there were increases in plasma creatinine, kidney weight and urinary protein at doses ≥150 mg/kg.

Changes to the gastrointestinal (GI) tract ranged from minimal to slight epithelial hypertrophy/hyperplasia to ulcer. The incidence and severity of these findings were dose-related. In studies with a recovery period, the changes were improved or reversed.

The pseudo-allergic reaction in dogs occurred at ≥15 mg/kg (>300 times the human clinical exposure). This reaction was characterized by reddening and swelling of the ears; the circumocular region; as well as the upper lips; and included vomiting. The pseudo-allergic reaction was associated with increases in circulating histamine concentrations. Similar reactions were noted in the monkey after intravenous (IV) administration of 40 mg/kg; however, there were no increases in plasma histamine. The no-observed-adverse-effect-level (NOAEL) in the dog was 9 mg/kg with a Cmax of 165 times that associated with human clinical exposure at the recommended therapeutic dose.

Linagliptin had no effects on heart rate, blood pressure, or electrocardiogram (ECG) evaluations in monkeys after oral administration of doses up to 300 mg/kg.

Genotoxicity

Linagliptin was not mutagenic or clastogenic in the in vitro Ames bacterial assay, the in vitro cytogenetics assay in primary human lymphocytes, and in the in vivo micronucleus assay in rats.

Carcinogenicity

Linagliptin showed no evidence of being carcinogenic in the 2-year carcinogenicity studies in rats and mice. The systemic exposure (AUC) at the high doses provided more than 200 times the human clinical exposure (AUC) at the recommended therapeutic dose.

Reproductive and Developmental Toxicity

No adverse effects on the fertility and early embryonic development were observed with rats at doses up to 240 mg/kg (approximately 900 times the human clinical exposure).

In the embryo-foetal development studies, linagliptin was not teratogenic at the highest doses administered (240 mg/kg in rats and 150 mg/kg in rabbits). At the 240 mg/kg dose in rats, minor maternal toxicity was reported. There was a slightly increased resorption rate, slight retardation of skeletal ossification, and also a slightly increased incidence of flat and thickened ribs. Administration of 25 and 150 mg/kg to pregnant rabbits resulted in decreased mean body weight gain and decreased food consumption at 150 mg/kg. At 150 mg/kg, linagliptin treatment was associated with intrauterine death, runts (foetuses weighing less than 65% of the weighted control mean values) and an increased incidence of visceral and skeletal variations.

In a pre- and post-natal development toxicity study in rats, treatment of the pregnant dams at 300 mg/kg (approximately 1,500 times human clinical exposure) during gestation and lactation caused decreased maternal body weight gain and food consumption. The first filial generation of dams treated at 300 mg/kg also showed reduced body weight during lactation and weaning. Their physical post-natal development proceeded in a normal range, except for delayed descensus testis and delayed preputial separation. These effects correlated with reduced body weight and were attributed to general growth retardation. The NOAEL was 30 mg/kg for both maternal and offspring toxicity.

3.2.4 Summary and Conclusion

The pharmacology and toxicology studies for this drug submission are considered acceptable. The effects of linagliptin have been evaluated in a comprehensive toxicology program of studies covering all endpoints appropriate for this indication and patient population. In the general toxicology studies, the doses selected span the range from no-effect doses to dose-limiting toxicity or doses associated with multiples of exposures exceeding 25-times the exposure in humans. Overall, the pharmacology and toxicology studies support the use of Trajenta™ for the proposed indication.

3.3 Clinical basis for decision

3.3.1 Pharmacodynamics

The plasma DPP-4 activity was inhibited in a dose-dependent manner after single-dose administration of linagliptin. Concentrations of approximately 2-3 ng/mL (4-6 nmol/L) are expected to lead to 80% inhibition of DPP-4 activity after single-dose administration, as well as on Day 1 and Day 12 of multiple-dose administration. At steady-state, plasma DPP-4 activity was inhibited over 24 hours by more than 80% in most patients receiving 5 mg linagliptin once daily. Linagliptin glucose-dependently increased insulin secretion and lowered glucagon secretion.

3.3.2 Pharmacokinetics
Absorption

Linagliptin demonstrated non-linear pharmacokinetics (PK) with a less than dose-proportional increase in plasma concentrations in the dose range of 1 to 10 mg, which includes the therapeutic 5 mg dose. As a consequence, the PK parameters are concentration dependent due to the non-linearity exhibited by linagliptin.

Linagliptin was rapidly absorbed with maximum linagliptin plasma concentrations (Cmax) attained at approximately 1.5 hours. The Cmax and AUC values increased in a less than dose-proportional manner. Plasma concentrations of linagliptin declined in a triphasic manner with a long terminal half-life (>100 hours); mostly related to the saturable binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The accumulation half-life of linagliptin, as determined from accumulation after oral administration of multiple doses of 5 mg linagliptin, was approximately 12 hours.

Distribution

As a result of tissue binding, the mean apparent volume of distribution at steady-state following a single 5 mg IV dose of linagliptin to healthy subjects was approximately 1,110 L, indicating that linagliptin extensively distributes to the tissues.

Metabolism

In vitro studies indicated that linagliptin is a substrate of P-gp and CYP3A4.

Following oral administration, the majority (approximately 90%) of linagliptin was excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite.

Excretion

Linagliptin was mainly eliminated by the liver. Renal excretion was a minor elimination pathway of linagliptin at therapeutic dose levels. Renal clearance at steady-state was approximately 70 mL/min.

Drug-Drug Interactions

Linagliptin does not have a strong potential for pharmacological interactions. Linagliptin has a moderate binding potency for plasma proteins. Also, while linagliptin is a substrate and weak inhibitor of P-gp and CYP3A4, CYP3A4 represents only a minor elimination pathway. Linagliptin was studied for drug-drug interactions with other oral antidiabetic agents; potent P-gp and CYP3A4 inhibitor, inducer and substrate drugs; drugs with a low therapeutic index; and a combination oral contraceptive. No clinically meaningful interactions occurred, except in the case of co-administration with the potent P-gp/CYP3A4 inducer, rifampicin. Co-administration of rifampicin decreased the bioavailability of linagliptin to a degree that could have compromised efficacy. Therefore, in cases where co-administration of potent CYP3A4/P-gp inducers result in unsatisfactory decreases in glucose levels, a change of the P-gp/CYP3A4 inducer to a non P-gp/CYP3A4 inducing compound or a change of linagliptin to another oral antidiabetic should be considered.

Special Populations

Renal Impairment

Based on PK studies, under steady-state conditions, PK characteristics in patients with mild and moderate renal impairment were comparable to those of subjects with normal renal function. Even though the PK studies did not show clinically-relevant effects of severe renal impairment with type 2 diabetes, there is a lack of clinical experience in this population to support the long-term safety. Therefore, use of Trajenta™ in patients with severe renal impairment and end-stage renal disease is not recommended.

Hepatic impairment

After a single dose of linagliptin, exposure of linagliptin was comparable in all liver impairment groups and showed no tendency to increase with decreasing hepatic function. After multiple dosing, general PK characteristics were comparable between healthy subjects and patients with mild or moderate hepatic impairment. There was no indication of any impact of hepatic impairment on the pharmacokinetics of linagliptin. However, no conclusive interpretation of the results was possible for patients with severe liver impairment due to the lack of results in steady-state conditions for this group. Use of Trajenta™ in patients with severe hepatic impairment is not recommended due to lack of clinical experience.

3.3.3 Clinical Efficacy
Monotherapy

The efficacy of Trajenta™ monotherapy in type 2 diabetic patients with insufficient glycaemic control was evaluated in a 24-week, pivotal, multicentre, randomized, double-blind, placebo-controlled, Phase III study (Study 1218.16, n = 503). A total of 336 patients were treated with Trajenta™ 5 mg and 167 patients were treated with placebo. At baseline, mean HbA1c values were comparable between both treatment groups (8.0% placebo; 8.0% Trajenta™). Results of the study demonstrated a significant mean reduction in glycated haemoglobin (HbA1c) at Week 24 in the Trajenta™ 5 mg treatment group, with changes from baseline of -0.44% compared to an increase of 0.25% for placebo. These findings were supported by other secondary efficacy endpoints; fasting plasma glucose, 2-hour post-prandial plasma glucose, and percentage of patients who achieved the target HbA1c of <7.0%. Body weight did not differ significantly between the two treatment groups.

The use of Trajenta™ as monotherapy in patients with metformin intolerance or contraindication was supported by an 18-week non-pivotal study; a multicentre, randomized, double-blind, placebo-controlled study (Study 1218.50, n = 227). A total of 151 patients were treated with Trajenta™ 5 mg and 76 patients were treated with placebo. At baseline, mean HbA1c values were comparable between both treatment groups (8.06% placebo; 8.11% Trajenta™). Data from this study demonstrated a significant mean reduction in HbA1c at Week 18 in the Trajenta™ 5 mg treatment group, with changes from baseline of -0.44% compared with an increase of 0.14% for the placebo group. These findings were supported by other secondary efficacy endpoints; fasting plasma glucose, post-prandial plasma glucose, and the percentage of patients who achieved the target HbA1c of <7.0%.

Combination Therapy with Metformin

The efficacy of Trajenta™ (5 mg once daily) as add-on therapy to metformin in type 2 diabetic patients with insufficient glycaemic control despite metformin therapy was demonstrated in a pivotal, 24-week, randomized, double-blind, placebo-controlled, parallel group study (Study 1218.17, n = 701). Of the 701 patients, 524 patients were treated with Trajenta™. Treatment with Trajenta™ in combination with metformin provided a significant improvement in HbA1c, compared to placebo in combination with metformin. At baseline, mean HbA1c values were comparable between both treatment groups (8.0% placebo; 8.1% Trajenta™). After 24 weeks of randomized treatment, the adjusted mean change for the Trajenta™ group was -0.49%, and 0.15% for the placebo group. The primary efficacy endpoint, the HbA1c placebo-adjusted mean change from baseline to Week 24 in HbA1c, was -0.64% (-0.78, -0.50) for the Trajenta™ group (baseline HbA1c was 8.09% in the Trajenta™ group). The secondary efficacy endpoints (fasting plasma glucose, categorical efficacy response, 2-hour post-prandial glucose, and use of rescue medication) supported the results of the primary efficacy analysis. There were no differences between the Trajenta™ and placebo groups with respect to change in body weight and waist circumference.

Combination Therapy with Sulfonylurea

The efficacy of Trajenta™ (5 mg once daily) as add-on therapy to sulfonylurea in type 2 diabetic patients with insufficient glycaemic control despite sulfonylurea therapy was demonstrated in a pivotal, 18-week, randomized, double-blind, placebo-controlled, parallel-group study (Study 1218.35, n = 161). At baseline, mean HbA1c values were comparable between both treatment groups (8.6% placebo; 8.6% Trajenta™). The primary efficacy endpoint, the placebo-adjusted mean change from baseline in HbA1c after 18 weeks of treatment, was observed to be -0.47% (p<0.0001) for the Trajenta™ group (baseline HbA1c was 8.61% in the Trajenta™ group). These findings were supported by the secondary efficacy variables (<7% HbA1c; and at least 0.5% reduction in HbA1c), as well as, the proportion of patients requiring rescue therapy. The secondary efficacy endpoint, fasting plasma glucose, did not demonstrate a significant difference between the Trajenta™ and placebo groups. Body weight and waist circumference did not differ significantly between the two groups.

Combination Therapy with Metformin and a Sulfonylurea

A 24-week, pivotal, multicentre, randomized, double-blind, placebo-controlled Phase III study (Study 1218.18, n = 1058) was conducted to evaluate the efficacy of Trajenta™ 5 mg compared to placebo, in patients not sufficiently treated with a combination with metformin and a sulfonylurea. At baseline, mean HbA1c values were comparable between both treatment groups (8.14% placebo; 8.15% Trajenta™). In this study, 792 patients treated with Trajenta™ 5 mg demonstrated significant mean reduction in HbA1c at Week 24 with changes from baseline of -0.72% compared with a decrease of 0.1% for placebo. These findings were supported by other secondary efficacy endpoints; fasting plasma glucose, 2-hour post-prandial plasma glucose, and percentage of patients who achieved a target HbA1c of <7.0%. No significant difference in change in body weight was observed between the two treatment groups.

Initial Combination Therapy with Pioglitazone

Study 1218.15 studied Trajenta™ as initial combination treatment with pioglitazone. This study was not designed to support an indication of add-on treatment to pioglitazone. Introducing two agents concurrently does not represent a favourable risk/benefit profile as it is difficult to monitor response, both in terms of efficacy and safety. Study 1218.15, in addition to enrolling drug naïve patients, also enrolled patients who were pretreated with one or more oral antidiabetic agents. The design of this study does not permit an assessment of whether patients on background treatment to start would have benefitted from switching to two new agents [that is (i.e.) Trajenta™ and pioglitazone] versus (vs.) staying on their original agent [for example (e.g.) metformin] and adding one additional agent sequentially. Therefore, the use of Trajenta™ as initial combination treatment with pioglitazone is unacceptable based on the data provided.

Long-term Efficacy

An interim analysis was performed on an uncontrolled, open-label, extension study (Study 1218.40, n = 2124), conducted in patients who continued treatment after completing the 24 weeks of treatment in the 4 placebo-controlled studies (Studies 1218.15, 1218.16, 1218.17, 1218.18). All patients received Trajenta™ 5 mg as monotherapy or as an add-on to the background therapy they took in the previous study. The treatment duration was 78 weeks, i.e., patients who completed this study received Trajenta™ 5 mg for either 78 weeks (patients who received placebo in the initial study) or 102 weeks (patients who received Trajenta™ in the initial study).

In patients who had been randomized to Trajenta™ in the preceding studies, the glucose-lowering effect of Trajenta™ achieved during the 24 weeks of treatment in the previous studies was sustained for up to 42 weeks of treatment in the present study. In patients who were previously treated with placebo, a decrease in HbA1c and fasting plasma glucose was observed.

3.3.4 Clinical Safety

In the placebo-controlled studies, 3,749 patients were included and 2,566 patients were treated with the therapeutic dose of Trajenta™ 5 mg. A total of 2,360 patients were exposed to Trajenta™ 5 mg once daily for ≥12 weeks.

Adverse events (AE) were analysed and displayed based on the respective treatment regimens (monotherapy, combination therapy with metformin, combination therapy with sulfonylurea, and combination therapy with meformin plus sulfonylurea).

Monotherapy

Treatment with Trajenta™ appeared to be safe and well-tolerated. In the pivotal Study 1218.16 (described in section 3.3.3 Clinical Efficacy) more than half of the patient population was reported with AEs (58.7% in the placebo group versus 52.4% in the Trajenta™ group). The majority of these events were mild or moderate in intensity. The System Organ Class (SOC) in which AEs were reported with a numerically higher frequency in the Trajenta™ group than in the placebo group were: blood and lymphatic system disorders (2.1% Trajenta™, 1.2% placebo); nervous system disorders (4.5% Trajenta™, 2.4% placebo); eye disorders (2.1% Trajenta™, 1.2% placebo); cardiac disorders (3.6% Trajenta™, 0.6% placebo); vascular disorders (5.1% Trajenta™, 1.2% placebo); respiratory, thoracic and mediastinal disorders (3.9% Trajenta™, 1.2% placebo); skin and subcutaneous tissue disorders (4.5% Trajenta™,1.8% placebo); and musculoskeletal and connective tissue disorders (9.5% Trajenta™, 6.0% placebo). There was an imbalance between treatment groups at baseline regarding cardiac disorders (10.8% placebo, 14.3% Trajenta™); skin and subcutaneous tissue disorders (3.0% placebo, 5.1% Trajenta™); and vascular disorders (24.0% placebo, 26.5% Trajenta™); and during the study, these events had a higher frequency in the Trajenta™ group. The incidence of hypoglycaemic events during treatment with Trajenta™ was low. There were no apparent adverse trends with respect to pancreatitis, hepatic or renal failure.

In the non-pivotal study (Study 1218.50), no major safety concerns were identified in the Trajenta™ treatment group, and the safety profile was comparable to that of the placebo group.

Combination Therapy with Metformin

Study 1218.17 (described in section 3.3.3 Clinical Efficacy) showed no significant safety trends specific to the results of this study. Overall, there were higher proportions of patients treated with Trajenta™ with AEs in the following SOC categories, compared to those that were treated with placebo: musculoskeletal/connective tissue disorders (11.1% Trajenta™, 7.9% placebo); respiratory, thoracic and mediastinal (4.9% Trajenta™, 2.8% placebo); nervous system disorders (6.9% Trajenta™, 5.1% placebo); skin and subcutaneous disorders (3.4% Trajenta™, 2.8% placebo); cardiac (2.3% Trajenta™, 0.6% placebo); and injury, poisoning and procedural complications (4.8% Trajenta™, 2.3% placebo).

The individual AEs which occurred at a frequency of at least 1% greater in the Trajenta™ group compared to the placebo group were dizziness (1.9% Trajenta™, 0.6% placebo) and palpitations (1% Trajenta™, 0% placebo). The laboratory analyses did not show any significant differences between the placebo and the Trajenta™ groups.

Combination Therapy with Sulfonylurea

The safety of Trajenta™ as add-on therapy to sulfonylurea was demonstrated in the pivotal Study 1218.35 (described in section 3.3.3 Clinical Efficacy). No significant safety trends specific to the results of this study were identified. The SOCs in which AEs were reported in a greater proportion in the Trajenta™ group than in the placebo group were as follows: infections and infestations (12.4% Trajenta™, 4.8% placebo); gastrointestinal disorders (6.8% Trajenta™, 3.6% placebo); respiratory, thoracic and mediastinal disorders (3.7% Trajenta™, 0% placebo); investigations (3.7% Trajenta™, 0% placebo); skin and subcutaneous tissue disorders (2.5% Trajenta™, 1.2% placebo); vascular disorders (2.5% Trajenta™, 1.2% placebo); cardiac disorders (1.9% Trajenta™, 0% placebo); injury, poisoning and procedural complication (1.9% Trajenta™, 1.2% placebo); and hepatobiliary disorders (0.6% Trajenta™, 0% placebo). Individual AEs which occurred in greater frequency, by at least 1%, in the Trajenta™ group (compared to the placebo group) were as follows: cataract [2 (1.2%) Trajenta™, 0% placebo]; vitreous hemorrhage [2 (1.2%) Trajenta™, 0% placebo]; nausea [2 (1.2%) Trajenta™, 0% placebo]; vomiting [2 (1.2%) Trajenta™, 0% placebo]; nasopharyngitis [7 (4.3%) Trajenta™, 1 (1.2%) placebo]; sinusitis [2 (1.2%) Trajenta™, 0% placebo]; urinary tract infection [0% placebo; 5 (3.1%) Trajenta™,]; blood triglycerides increased [2 (1.2%) Trajenta™, 0% placebo]; hypertriglyceridemia [2 (1.2%) Trajenta™, 0% placebo]; gout [2 (1.2%) Trajenta™, 0% placebo]; cough [2 (1.2%) Trajenta™, 0% placebo]; cold sweat [2 (1.2%) Trajenta™, 0% placebo]; urticaria [2 (1.2%) Trajenta™, 0% placebo]; and hypertension [2 (1.2%) Trajenta™, 0% placebo]. The laboratory analyses did not show any significant differences between the placebo and Trajenta™ groups.

Combination Therapy with Metformin and a Sulfonylurea

In the pivotal Study 1218.18 (described in section 3.3.3 Clinical Efficacy), 157 patients, (59.7%) and 525 patients, (66.3%) were reported with AEs in the placebo group and the Trajenta™ group, respectively. Adverse events of severe intensity were reported for few patients in both groups (1.5% placebo; 2.4% Trajenta™), otherwise all AEs were mild or moderate in intensity.

The SOCs that were reported at a higher frequency in the Trajenta™ group compared to the placebo group were: metabolism and nutrition disorders; hypoglycaemia (31.1% Trajenta™, 25.9% placebo); musculoskeletal and connective tissue disorders (12.2% Trajenta™, 9.1% placebo); respiratory, thoracic and mediastinal disorders (4.2% Trajenta™, 2.7% placebo); and vascular disorders (4.3% Trajenta™, 2.3% placebo). Drug-related hypoglycaemia was approximately two-folds higher in the Trajenta™ group (14.5%) compared to the placebo group (7.6%). Most of these reported events were mild to moderate in intensity. Hypoglycaemia leading to study discontinuation was reported at a low frequency (0.6% in the Trajenta™ group).

Long-term Safety

Interim analysis of open-label extension study

An interim analysis was performed on an uncontrolled, open-label, extension study (Study 1218.40, n = 2124), conducted in patients who continued treatment after completing the 24 weeks of treatment in four placebo-controlled studies (Studies 1218.15, 1218.16,1218.17, 1218.18). Patients continued their treatment with Trajenta™ 5 mg as monotherapy (Study 1218.16) or plus 30 mg pioglitazone as initial combination (Study 1218.15), or in addition to either metformin (Study 1218.17), or metformin plus sulfonylurea background therapy (Study 1218.18). Patients who received placebo in the previous studies were treated with 5 mg Trajenta™.

Until the cut-off date for this interim analysis, about 45% of the patients were exposed to Trajenta™ for >42 to 54 weeks. This study did not include an active comparator arm for long-term safety comparison. The most frequently reported AEs were in metabolism and nutrition system disorders [30.3%; hyperglycaemia (16.3%) and hypoglycaemia (9.7%)]; infections and infestations (26.1%); musculoskeletal and connective tissue disorders (13.4%); and skin and subcutaneous tissue disorders (4.7%). Hypoglycaemia was frequently experienced by patients who received a double background therapy of metformin and sulfonylurea (24.7%, Study 1218.18). Five patients died during the study; all deaths were considered not to be related to the study drug intake. Of the 5 patients that died, 3 patients died during the treatment period. The causes of death were cardio-respiratory arrest, pulmonary embolism, and infectious, polypous and ulcerous endocarditis of the aortic valve. The other two patients died during the post-treatment period due to cardio-respiratory arrest and metastatic pulmonary adenocarcinoma.

Long-term integrated safety analysis in controlled and uncontrolled studies

The analysis of long-term safety is complemented by SAF-5, a grouping that was based on data from controlled and uncontrolled studies. This long-term analysis included 2,387 patients with type 2 diabetes who received Trajenta™ 5 mg for at least 52 weeks and 536 patients who received Trajenta™ 5 mg for at least 78 weeks. The most frequently reported adverse events were: hyperglycaemia (13.2%); nasopharyngitis (11.3%); hypoglycaemia (10.8%); upper respiratory tract infection (6.8%); headache (4.9%); back pain (4.8%); hypertension (4.3%); arthralgia (4.2%); urinary tract infection (4.1%); and diarrhoea (4.0%). Cardiac disorders were reported by 4.8% of patients, vascular disorders by 7.0% of patients (4.3% hypertension), and skin and subcutaneous tissue disorders by 8.6% of patients. Adverse events were analyzed over time. In general, the largest proportion of events occurred at the beginning of the randomized treatment period within the first 26 weeks with declining incidences over time and no particular trend towards any SOC. Of the drug-related AEs, hyperglycemia and hypoglycaemia were the most frequent AEs.

There were 5 fatal cases in this safety grouping. All deaths were considered not to be related to study drug intake.

During the clinical development program of Trajenta™, 8 cases of pancreatitis were reported out of 4,687 patients who received Trajenta™ 5 mg and another 3 cases were reported in the post-treatment period. Although the relationship to Trajenta™ treatment was not identified and history of pancreatitis was identified in some of these cases, a class effect could not be excluded.

No particular trends toward cardiac, renal or hepatic adverse drug reactions were noted.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Type 2 diabetes is an increasingly prevalent disease affecting millions of people worldwide. This disease is characterized by multiple metabolic abnormalities and is associated with several macrovascular and microvascular complications which in turn result in a reduction in life expectancy and an increase in risk for cardiovascular disease.

Trajenta™ has been shown to be effective in the treatment of patients with type 2 diabetes, as monotherapy or as an add-on to metformin and/or sulfonylurea therapy. The superiority over the placebo group was demonstrated for primary and secondary endpoints. Trajenta™ provided significant reductions in HbA1c, as well as significant improvements in fasting plasma glucose and post-prandial plasma glucose concentrations. Data from the long-term extension study, demonstrated that the glucose-lowering effect achieved during the 24 weeks of treatment was sustained for up to 42 weeks.

Trajenta™ is well-tolerated with an acceptable safety profile which is comparable to placebo. The most frequent drug-related AEs were hyperglycaemias and hypoglycaemia. Most of the events of hypoglycaemia were mild or moderate in intensity and were seen in patients who received sulfonylurea and metformin background therapy.

In conclusion, the benefits of using Trajenta™ for treatment of patients with type 2 diabetes as monotherapy or add-on to metformin and/or a sulfonylurea therapy outweighs the associated risks for this patient population.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Trajenta™ is favourable in adult patients with type 2 diabetes mellitus to improve glycaemic control.

Monotherapy

  • In conjunction with diet and exercise in patients for whom metformin is inappropriate due to contraindications or intolerance.

Combination Therapy

  • In combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
  • In combination with a sulfonylurea when diet and exercise plus a sulfonylurea alone do not provide adequate glycaemic control.
  • In combination with metformin and a sulfonylurea when diet and exercise plus metformin and a sulfonylurea do not provide adequate glycaemic control.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: TrajentaTM

Submission MilestoneDate
Pre-submission meeting2010-06-08
Submission filed:2010-08-17
Screening
Screening Acceptance Letter issued:2010-10-01
Review
Quality Evaluation complete:2011-07-22
Clinical Evaluation complete:2011-04-27
Biostatistics Evaluation complete:2011-02-03
Labelling Review complete:2011-07-22
Notice of Compliance issued by Director General:2011-07-28