Subdermal Implant-bioabsorbable Oxandrolone Pellet For Rehabilitation Following Anterior Cruciate Ligament (ACL) Surgical Reconstruction

Official title

Randomized, Multicenter, Double-blind, Parallel, Placebo-controlled Study to Investigate the Safety and Exploratory Efficacy of the Absorbable Oxandrolone Implant as an Adjuvant Treatment in Rehabilitation Following Anterior Cruciate Ligament (ACL) Surgical Reconstruction (IMOX Study)

Overview

Rehabilitation of knee stability and function after anterior cruciate ligament (ACL) reconstruction is slow and costly. The use of anabolic steroids, such as oxandrolone, may aid in the recovery of muscle mass and strength, as well as functional capacity. Oxandrolone, derived from dihydrotestosterone, has high anabolic activity and low androgenic activity (a 13:1 ratio), making it more effective in promoting weight gain with fewer side effects compared to other steroids. Registered by the FDA and previously by ANVISA (National Health Surveillance Agency (Brazil), it is indicated for cases of post-trauma or post-surgery weight loss. The subdermal use of oxandrolone implants is proposed to release the drug directly into the bloodstream, improving efficacy and reducing issues related to oral administration. This study evaluates the safety and tolerability of the absorbable subdermal oxandrolone implant for 24 weeks versus placebo implant in both men and women as an adjuvant treatment during rehabilitation following anterior cruciate ligament (ACL) surgical reconstruction. The serum and pharmacokinetic profile of the oxandrolone implant will be monitored.

Detailed description

This is a phase II, randomized, double-blind, placebo-controlled, multicenter clinical study designed to evaluate the safety and tolerability profile of the absorbable oxandrolone implant as an adjuvant treatment in rehabilitation following anterior cruciate ligament (ACL) reconstruction surgery. The primary safety outcome will be the incidence of serious adverse events (SAEs) related do treatment collected through spontaneous reports and/or clinical findings over 24 weeks after randomization (subdermal insertion of the absorbable oxandrolone implant). The effectiveness of absorbable oxandrolone implants in the rehabilitation of patients after surgical ACL reconstruction will be evaluated in an exploratory manner, based on their effects on the recovery of muscle mass, muscle strength, and functional capacity.

Interventions

• Drug Oxandrolone
  Absorbable oxandrolone implant (subdermal insertion) Men: 400 mg oxandrolone (two 200 mg oxandrolone implants each) Women: 200 mg oxandrolone (one 200 mg oxandrolone implant)
• Drug Placebo
  Absorbable placebo implant (excipients; subdermal insertion) Men: 400 mg placebo (two 200 mg placebo implants each) Women: 200 mg placebo (one 200 mg placebo implant)

Primary outcome measures

• Combination of serious adverse events (SAEs) related to treatment accumulated within 24 weeks of oxandrolone or placebo pellet insertion and collected through spontaneous reporting and/or clinical findings [Time frame: From randomization to the end of study on Week 24.]

Secondary outcome measures (10)

• Participants who experience androgenization [Time frame: At pre-insertion and 4, 12 and 24 weeks after randomization]
• Biochemical profile [Time frame: At pre-insertion, 4, 12, and 24 weeks after randomization]
• Metabolic Profile [Time frame: At pre-insertion, 4, 12, and 24 weeks after randomization]
• Hormonal Profile [Time frame: At pre-insertion, 4, 12, and 24 weeks after randomization]
• Hemostasis Parameters [Time frame: At pre-insertion, 4, 12, and 24 weeks after randomization]
• Total serum oxandrolone concentration [Time frame: Pre-insertion of the oxandrolone implant; various times after the insertion of the oxandrolone implant and 24 hours; 1, 2, 3, 4, 8, 12, 16, 20, and 24 weeks.]
• Area under the curve (AUC) [Time frame: Pre-insertion of the oxandrolone implant and various times after the insertion of the oxandrolone implant: 24 hours; 1, 2, 3, 4, 8, 12, 16, 20, and 24 weeks.]
• Maximum concentration (Cmax) [Time frame: Pre-insertion of the oxandrolone implant and various times after the insertion of the oxandrolone implant: 24 hours; 1, 2, 3, 4, 8, 12, 16, 20, and 24 weeks.]
• Time to reach maximum concentration (tmax) [Time frame: Pre-insertion of the oxandrolone implant and various times after the insertion of the oxandrolone implant: 24 hours; 1, 2, 3, 4, 8, 12, 16, 20, and 24 weeks.]
• Half Life (t1/2) [Time frame: Pre-insertion of the oxandrolone implant and various times after the insertion of the oxandrolone implant: 24 hours; 1, 2, 3, 4, 8, 12, 16, 20, and 24 weeks.]

Eligibility criteria

Inclusion criteria

For male and female participants:

• Ability to confirm voluntary participation and approve the Informed Consent Form;
• Men and women aged 18 to 60 years (inclusive);
• Body weight between 50-120 kg for men and 40-90 kg for women;
• BMI ≤34.9 kg/m²;
• Complete ACL rupture visualized by pre-operative magnetic resonance imaging (MRI);
• Having undergone arthroscopic knee surgery for anterior cruciate ligament (ACL) coverage using an autologous hamstring tendon graft;
• Presenting with an isolated ACL injury or combined with ligamentous, meniscal, or cartilage lesions visualized by MRI, provided they do not interfere with the rehabilitation protocol.
• Classification as very active, active, or irregularly active type A according to the International Physical Activity Questionnaire (IPAQ), based on pre-ACL injury physical activity;
• Adherence to the rehabilitation protocol, having initiated postoperative physiotherapy treatment;
• Functional range of motion from 0 to 120º and ability to ambulate without crutches;
• Blood pressure in the seated position in the doctor's office <180/95 mmHg;
• Hematocrit ≤ 50%;
• ALT less than three times the upper limit of normal;
• Serum creatinine <2 mg/dL;
• Total bilirubin < 3.0 mg/dL;
• Albumin ≥ 3.5 g/dL;

For male participants only:

\- Total PSA ≤ 4.1 ng/mL.

Exclusion criteria

For female participants only:

• Confirmed or suspected pregnancy;
• History of childbirth, abortion, or lactation in the last 3 months;
• Refusal to use permitted contraceptive methods during the study and for 90 days after the end of participation in the study, unless surgically sterile or expressly declaring themselves exempt from the risk of pregnancy due to not engaging in sexual activity or engaging in non-reproductive activity;
• Clinical signs of hyperandrogenization characterized by: hirsutism defined by a Ferriman-Gallwey score ≥ 8; or alopecia defined by hair loss of at least 50% of the participant's normal hair, which is not obvious from a distance but is only noticeable upon closer inspection; a different haircut may be necessary to cover the hair loss, but does not necessarily require a wig or hairpiece to camouflage it; or Grade 5 acne defined by a predominance of inflammatory acne lesions in the facial area;
• Polycystic Ovary Syndrome;
• Known or suspected breast carcinoma;

For male participants only:

\- Known or suspected carcinoma of the prostate or male breast;

For male and female participants:

• Previous serious injury or history of surgery on the lower limbs;
• Knee injury more than 36 months ago;
• Unstable longitudinal meniscal tear requiring repair where subsequent postoperative treatment (e.g., immobilization and range of motion limitation) interferes with the rehabilitation protocol;
• Meniscus suture during ACL reconstruction;
• Use of patellar, quadriceps, or other hamstring tendon grafts during ACL reconstruction;
• Known contraindication to hormone use;
• Any condition that worsens under hormone treatment;
• Personal history of deep vein thrombosis (DVT);
• Known coagulopathy;
• Known chromosomal disorders;
• Hypersensitivity to anabolic androgenic steroids;
• Previous treatment failure with Oxandrolone;
• Use of testosterone (or analogues) and other anabolic androgenic steroids in any pharmaceutical form in the last 3 months;
• Pituitary tumor;
• Creatinine levels >2 mg/dL or history of chronic kidney disease;
• Myocardial infarction in the last 6 months;
• Uncontrolled dyslipidemia;
• Uncontrolled diabetes;
• Patients with chronic obstructive pulmonary disease (COPD) unresponsive to bronchodilators;
• Any contraindication to magnetic resonance imaging (MRI);
• Claustrophobia;
• Irregularly active type B or sedentary classification on the International Physical Activity Questionnaire (IPAQ), based on pre-ACL injury physical activity;
• Athlete engaged in paid physical activity;
• Known psychiatric diagnosis, including disorder Major or persistent depressive disorder, bipolar disorder, anxiety, social phobia, specific phobias or obsessive-compulsive disorder, psychotic disorder, personality disorder, eating disorder, neurocognitive disorders, and developmental or somatoform disorders (somatization or hypochondria);
• Presence of voiding disorder;
• Known diagnosis of fibromyalgia;
• Current smoking;
• History of drug abuse;
• Participation in other clinical trial protocols in the last 30 days;
• Participant who, in the investigator's opinion, presents other conditions or clinical or laboratory alterations that make them ineligible to participate in the study;
• The participant came to meet any exclusion criterion verified at the Selection Visit (SV/V1);
• Presenting postoperative complications such as stiffness and/or healing in the knee requiring additional procedures.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Brazil · 6 centers

• Unimed Fortaleza — Fortaleza
• Faculdade Ciências Médicas de Minas Gerais (CMMG) — Belo Horizonte
• Centro de Oncologia do Paraná — Curitiba
• Unimed Brusque — Brusque
• Hospital e Maternidade Christóvão da Gama — Santo André
• Santa Casa de Santos — Santos

Publications

• Weber AE, Gallo MC, Bolia IK, Cleary EJ, Schroeder TE, Rick Hatch GF 3rd. Anabolic Androgenic Steroids in Orthopaedic Surgery: Current Concepts and Clinical Applications. J Am Acad Orthop Surg Glob Res Rev. 2022 Jan 4;6(1):e21.00156. doi: 10.5435/JAAOSGlobal-D-21-00156. PMID 34982051
• Orr R, Fiatarone Singh M. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs. 2004;64(7):725-50. doi: 10.2165/00003495-200464070-00004. PMID 15025546
• Thomas AC, Wojtys EM, Brandon C, Palmieri-Smith RM. Muscle atrophy contributes to quadriceps weakness after anterior cruciate ligament reconstruction. J Sci Med Sport. 2016 Jan;19(1):7-11. doi: 10.1016/j.jsams.2014.12.009. Epub 2015 Jan 13. PMID 25683732
• Bauman WA, Spungen AM, Collins JF, Raisch DW, Ho C, Deitrick GA, Nemchausky BA, Goetz LL, Park JS, Schwartz M, Merritt JL, Jayawardena V, Sandford P, Sabharwal S, Holmes SA, Nasar F, Sasaki R, Punj V, Zachow KF, Chua WC, Thomas MD, Trincher RC. The effect of oxandrolone on the healing of chronic pressure ulcers in persons with spinal cord injury: a randomized trial. Ann Intern Med. 2013 May 21;158 PMID 23689765
• Wu B, Lorezanza D, Badash I, Berger M, Lane C, Sum JC, Hatch GF 3rd, Schroeder ET. Perioperative Testosterone Supplementation Increases Lean Mass in Healthy Men Undergoing Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial. Orthop J Sports Med. 2017 Aug 9;5(8):2325967117722794. doi: 10.1177/2325967117722794. eCollection 2017 Aug. PMID 28840147

Identifiers

NCT: NCT06974526 · IMOX

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗