A Phase I Study to Evaluate the Pharmacokinetic and Pharmacodynamic Profile of Intramuscular or Subcutaneous Injections of Levonorgestrel Butanoate (LB) for Female Contraception
Brief description: This is a Phase I multicenter, open-label, dose-ranging, three-dose PK and PD study of injectable LB administered as an IM or SQ injection at 40 mg, and subsequently at 50mg SQ and then 60 mg SQ depending on the preliminary pharmacokinetic and pharmacodynamic results obtained with 40 mg dosing.
Detailed description: This is a Phase I multicenter, open-label, dose-ranging, three-dose PK and PD study of injectable LB administered as an IM or SQ injection at 40 mg, and subsequently at 50 mg SQ and then 60 mg SQ depending on the preliminary pharmacokinetic and pharmacodynamic results obtained with 40 mg dosing. Healthy normal weight and healthy obese women will be enrolled and followed as outpatients until return to ovulation and normal menses. The participation time is estimated to be approximately nine months. During this study, subjects will undergo a screening period prior to enrollment to confirm normal ovulatory function, and then receive active treatment with injection of LB administered via IM or SQ injection. A dose of LB administered IM (40 mg) or SQ (40 mg) was selected for initial evaluation for this study. Subjects will undergo frequent study and safety evaluations and will have serum samples taken to evaluate drug levels and ovulatory function, in addition to a transvaginal ultrasound (TVUS) at selected visits. Follow-up will continue until normal ovulatory cycles resume. Based upon detailed studies in non-human primates and our experience with the 40mg dose groups, it is expected that most subjects will resume menstrual cycles within 12 - 26 weeks after the injection. Subjects will continue to be followed for one normal cycle after the return of menses. This dose-ranging, PK/PD study will be conducted at seven of the female Contraceptive Clinical Trials Network (CCTN) sites in the U.S. and will enroll approximately 136 women who demonstrate normal ovulatory function during the baseline cycle. Enrollment will be stratified to target that 50% of the subjects have a BMI >30 kg/m^2 and <40 kg/m^2 and approximately 50% of subjects have a BMI <30 kg/m^2 in each dose group. LB injections will be administered at the study site by a trained research nurse or physician. The SQ injections should be done slowly under the skin in the abdomen to ensure drug is dispensed into the tissue layer between the skin and the muscle following standard procedures for subcutaneous injections. For IM injections, the staff should inject LB slowly in the deltoid avoiding the injection into blood vessels following standard procedures for intramuscular injections. (The SQ injection may be given in a different location than the abdomen and the IM injection in a different location than the deltoid with the approval of the Medical Monitor.) The study subject will be observed for at least 30 minutes after the injection before release from the study site. The different combinations of doses and methods of administration (IM or SQ) will be given in sequential stages, using two different LB concentrations (20 mg/mL or 70 mg/mL) as described below. Enrollment Stage A: 40 mg IM with 20 mg/ml concentration (27 subjects [18 with BMI <30 kg/m^2; 9 with BMI >30 kg/m^2 and <40 kg/m^2]) Enrollment Stage B: 40 mg SQ with 20 mg/ml concentration (32 subjects [25 with BMI <30 kg/m^2; 7 with BMI >30 kg/m^2 and <40 kg/m^2]) Enrollment Stage B2: 40 mg SQ with 70 mg/ml concentration (32 subjects [21 with BMI <30 kg/m^2; 11 with BMI >30 kg/m^2 and <40 kg/m^2]) Enrollment Stage C: 50 mg IM with 70 mg/ml concentration (8 subjects [8 with BMI <40 kg/m^2]) Enrollment Stage D: 60 mg SQ with 70 mg/ml concentration (32 subjects [16 with BMI <30 kg/m^2; 16 with BMI >30 kg/m^2 and <40 kg/m^2]) Stages will be performed sequentially; PK/PD assessments will be performed. The target numbers for enrollment in each BMI category are approximate. Results of the preliminary pharmacokinetic and pharmacodynamic results for the three 40 mg dose groups support moving forward with a maximum dose of 60 mg rather than 70 mg SQ. However, after reviewing these results, the FDA recommended a SAD study with a 50 mg SQ dose before proceeding with 60 mg LB administered SQ. The following enrollment table reflects groups for this revised protocol.
Detailed description: This is a Phase I multicenter, open-label, dose-ranging, three-dose PK and PD study of injectable LB administered as an IM or SQ injection at 40 mg, and subsequently at 50 mg SQ and then 60 mg SQ depending on the preliminary pharmacokinetic and pharmacodynamic results obtained with 40 mg dosing. Healthy normal weight and healthy obese women will be enrolled and followed as outpatients until return to ovulation and normal menses. The participation time is estimated to be approximately nine months. During this study, subjects will undergo a screening period prior to enrollment to confirm normal ovulatory function, and then receive active treatment with injection of LB administered via IM or SQ injection. A dose of LB administered IM (40 mg) or SQ (40 mg) was selected for initial evaluation for this study. Subjects will undergo frequent study and safety evaluations and will have serum samples taken to evaluate drug levels and ovulatory function, in addition to a transvaginal ultrasound (TVUS) at selected visits. Follow-up will continue until normal ovulatory cycles resume. Based upon detailed studies in non-human primates and our experience with the 40mg dose groups, it is expected that most subjects will resume menstrual cycles within 12 - 26 weeks after the injection. Subjects will continue to be followed for one normal cycle after the return of menses. This dose-ranging, PK/PD study will be conducted at seven of the female Contraceptive Clinical Trials Network (CCTN) sites in the U.S. and will enroll approximately 136 women who demonstrate normal ovulatory function during the baseline cycle. Enrollment will be stratified to target that 50% of the subjects have a BMI >30 kg/m^2 and <40 kg/m^2 and approximately 50% of subjects have a BMI <30 kg/m^2 in each dose group. LB injections will be administered at the study site by a trained research nurse or physician. The SQ injections should be done slowly under the skin in the abdomen to ensure drug is dispensed into the tissue layer between the skin and the muscle following standard procedures for subcutaneous injections. For IM injections, the staff should inject LB slowly in the deltoid avoiding the injection into blood vessels following standard procedures for intramuscular injections. (The SQ injection may be given in a different location than the abdomen and the IM injection in a different location than the deltoid with the approval of the Medical Monitor.) The study subject will be observed for at least 30 minutes after the injection before release from the study site. The different combinations of doses and methods of administration (IM or SQ) will be given in sequential stages, using two different LB concentrations (20 mg/mL or 70 mg/mL) as described below. Enrollment Stage A: 40 mg IM with 20 mg/ml concentration (27 subjects [18 with BMI <30 kg/m^2; 9 with BMI >30 kg/m^2 and <40 kg/m^2]) Enrollment Stage B: 40 mg SQ with 20 mg/ml concentration (32 subjects [25 with BMI <30 kg/m^2; 7 with BMI >30 kg/m^2 and <40 kg/m^2]) Enrollment Stage B2: 40 mg SQ with 70 mg/ml concentration (32 subjects [21 with BMI <30 kg/m^2; 11 with BMI >30 kg/m^2 and <40 kg/m^2]) Enrollment Stage C: 50 mg IM with 70 mg/ml concentration (8 subjects [8 with BMI <40 kg/m^2]) Enrollment Stage D: 60 mg SQ with 70 mg/ml concentration (32 subjects [16 with BMI <30 kg/m^2; 16 with BMI >30 kg/m^2 and <40 kg/m^2]) Stages will be performed sequentially; PK/PD assessments will be performed. The target numbers for enrollment in each BMI category are approximate. Results of the preliminary pharmacokinetic and pharmacodynamic results for the three 40 mg dose groups support moving forward with a maximum dose of 60 mg rather than 70 mg SQ. However, after reviewing these results, the FDA recommended a SAD study with a 50 mg SQ dose before proceeding with 60 mg LB administered SQ. The following enrollment table reflects groups for this revised protocol.