NICHD: SERVICE: CCTN LB PHASE 2B CLINICAL TRIAL: NON-SEVERABLE

Eastern Virginia Medical School, Norfolk VA

Investigators

Abstract

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) serves as the lead federal agency advancing research in fertility optimization. Within NICHD, the Contraceptive Development Program (CDP) under the Division of Population Health Research (DiPHR) is tasked with developing novel contraceptive methods for both men and women. CDP coordinates its research components to drive innovation in reproductive health, translating scientific discoveries into clinically viable products through public-private partnerships and technology transfer mechanisms. In fulfillment of its Title X legislative mandate, NICHD conducts clinical trials of new or improved drugs and devices to expand fertility optimization options, supporting individuals and families in making informed reproductive health decisions. Clinical evaluation of these novel contraceptive products is conducted through CDP’s Contraceptive Clinical Trials Network (CCTN), a group of clinical sites prequalified on the basis of experienced personnel and facilities using a full and open competitive IDIQ contract mechanism. The CCTN rigorously assesses the safety, efficacy, and tolerability of candidate drugs and devices across all phases of development—from first-in-human trials to Phase III. These trials not only generate the critical data required for FDA regulatory approval but also foster training opportunities for the next generation of clinical investigators in contraceptive science. As interest from private-sector investors grows, CDP is able to bridge scientific innovation with commercialization through public-private collaboration that directly impacts public health. Building on its mandate to advance fertility optimization and contraceptive innovation, NICHD’s Contraceptive Development Program (CDP) is supporting the clinical development of levonorgestrel butanoate (LB), a long-acting, progestin-only injectable contraceptive. This effort addresses a critical public health need: most currently available combined hormonal contraceptives are associated with an increased risk of venous thromboembolism (VTE), making them unsuitable or less desirable for many women—particularly those who are obese or have other risk factors. Consequently, there is a pressing need for estrogen-free, safe, and effective alternatives that provide long-term contraception without increasing thrombotic risk. As a pro-drug, LB delivers active levonorgestrel through slow hydrolysis following subcutaneous or intramuscular injection. Levonorgestrel is considered as a gold standard of safety in the hormonal contraceptive field. NICHD’s recent formulation efforts have focused on optimizing LB for subcutaneous administration, with improved stability, concentration, and extended duration of action. This new formulation enhances convenience through potential self administration, reduces the need for frequent clinic visits, and may offer better adherence than daily oral contraceptives or less predictable alternatives such as patches or implants. The ongoing dose-finding evaluation of LB at current CCTN sites has established a dose that demonstrates inhibition of ovulation for four months. If confirmed by evaluating this dose in women at risk of pregnancy, this duration of activity represents potential advancement over the three-month injection interval recommended for the existing injectable method, depot medroxyprogesterone acetate (DMPA). The low incidence of mood changes and weight gain observed with LB provide substantial encouragement that LB will have a high level of acceptability. To evaluate the safety and efficacy of this promising product, CDP is conducting a multicenter, open-label, Phase 2b trial (CCN021b) through its Contraceptive Clinical Trials Network (CCTN). The study will enroll approximately 180 healthy women between 18 and 35 years of age across six U.S. clinical sites. Participants will receive two injections of LB spaced four months apart, with follow-up lasting for 8 months of contraception followed by a recovery period to document the return of ovulation and menstruation. This study is designed to generate key data on contraceptive efficacy, safety, tolerability, and acceptability, supporting the development of LB as a potential new injectable contraceptive option with an excellent safety profile, a low incidence of side effects, and more predictable return to fertility relative to currently available methods. The objective for this acquisition is to continue CPD’s development of LB to address FDA regulatory requirements and transition to approval for a Phase 3 study. This study will be separated into 4 separate phases, with distinct aims and deliverables. The Government estimates the Contractor(s) to complete protocol finalization, regulatory approvals, start-up, and commencement of initial recruitment and enrollment in Phase A, optimization and continuation of recruitment, screening, and enrollment and initiation of follow-up of enrolled subjects, and finalization of regulatory requirements in Phase B, completion of follow-up and monitoring of active subjects, clinical follow-up, and data collection for all enrolled participants in Phase C, and exit, site close-out, completion of study reports and clinical summary report in Phase D. The estimated time for each Phase is outlined in the Technical Requirements below.