A Randomized, Double-Blind, Parallel-Group Study to Assess the Effects of Arbaclofen ER Tablets Compared With Placebo on Sperm Parameters in Male Subjects With Multiple Sclerosis

To Assess Effects of Arbaclofen ER Tablets Compared With Placebo on Sperm Parameters in Male Subjects With MS

Sponsors

Lead sponsor: Osmotica Pharmaceutical US LLC

Source Osmotica Pharmaceutical US LLC
Brief Summary

This study is designed to assess the effects of a therapeutic dose of arbaclofen extended release (ER) tablets compared with placebo on human sperm concentration, motility, and morphology in male subjects with multiple sclerosis (MS).

Detailed Description

Primary Objective:

The primary safety objective is to assess the effects of arbaclofen ER tablets (AERT) compared with placebo on sperm concentration from baseline to the end of 90 days of treatment in male subjects with MS.

Secondary Objectives:

The secondary safety objectives are to assess:

- The effects of AERT compared with placebo on the following sperm parameters from baseline to the end of 90 days of treatment in male subjects with MS:

- Semen volume and total sperm count per ejaculate;

- Sperm motility;

- Sperm morphology; and

- Plasma levels of reproductive hormones: Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone;

- The recovery of subjects with 50 % decrease in sperm parameters 90 days after the discontinuation of IP; and

- The safety and tolerability of IP.

Overall Status Withdrawn
Start Date July 2016
Completion Date January 2019
Primary Completion Date October 2018
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Measure of sperm concentration according to WHO guidelines 90 days of treatment
Secondary Outcome
Measure Time Frame
Measure of sperm motility according to the WHO guidelines 90 days of treatment
Measure of Plasma levels of FSH, LH, and total testosterone values and their respective change from baseline values will be summarized by visit 90 days of treatment
Measure of Semen volume per ejaculate according to the WHO guidelines 90 days of treatment
Measure of total sperm count per ejaculate according to the WHO guidelines 90 days of treatment
Measure of Sperm morphology according to the WHO guidelines 90 days of treatment
The recovery of subjects with 50% decrease in sperm parameters 90 days after the discontinuation of IP 90 days of treatment
Condition
Intervention

Intervention type: Drug

Intervention name: arbaclofen ER Tablets

Description: arbaclofen ER tablets, 10 mg, 15 mg, or 20 mg

Arm group label: Arbaclofen ER Tablets

Other name: AERT

Intervention type: Drug

Intervention name: Placebo for arbaclofen ER tablets

Description: matching placebo tablets to arbaclofen ER tablets 10 mg, 15 mg or 20 mg

Arm group label: Placebo for Arbaclofen ER Tablets

Other name: Placebo

Eligibility

Criteria:

Inclusion Criteria:

- For a subject to be eligible for participation in this study, all of the following criteria must be met at Screening:

1. Sign an informed consent form (ICF) indicating willingness and ability to participate in the study;

2. Be male and between 18 to 55 years old, inclusive, at the time of dosing;

3. Has an established diagnosis of MS for >6 months; subjects with all types of MS (relapsing remitting, secondary-progressive, primary-progressive, or neuromyelitis optica) can be enrolled in the study if they meet all other eligibility criteria;

4. Has spasticity in the extremities that requires daily treatment with anti-spasticity drugs in the judgment of the Investigator;

5. Is able to have an erection and antegrade ejaculation with or without the use of phosphodiesterase 5 inhibitors (sildenafil, tadalfil, etc.);

6. The average of each semen parameter (except volume) collected at Screening (Visits 1 and 2) will be calculated to determine if the subject meets the following sperm eligibility criteria:

1. Semen volume > or equal to 1.5 mL,

2. Total sperm per ejaculation > or equal to 15 million,

3. Sperm concentration > or equal to 10 million/mL,

4. Total sperm motility > or equal to 19%, and

5. White blood cell count <3 million/mL,

7. Concomitant use of baclofen is permitted during Screening, but subjects must stop baclofen on the day prior to randomization (Visit 3). All other prohibited concomitant medications (Appendix D) must be discontinued prior to randomization (Visit 3);

8. If receiving disease-modifying medications, these must have been at a stable dose for at least 3 months prior to randomization;

9. All other medications, including AMPYRA® (e.g., dalfampridine, fampridine, 4 aminopyridine), must have been at a stable dose for at least 3 months prior to randomization;

10. Absence of infections, peripheral vascular disease, contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement;

11. Has a creatinine clearance > or equal to 50 mL/min, as calculated by glomerular filtration rate using the Modification of Diet in Renal Disease formula;

12. Be able to swallow tablets whole;

13. Be willing to abstain from ejaculation for at least 3 days prior to the collection of each semen sample;

14. Subject and female partners must agree to use a birth control method while on IP and until 30 days following the last administration of IP; and

15. If acquisition of a semen sample requires participation of the subject's partner, that partner must sign an informed consent and agree to participate in the study.

Exclusion Criteria:

- Subjects will NOT be eligible for inclusion in the study if any of the following criteria apply:

1. Had an acute MS exacerbation requiring treatment within 6 weeks of Screening;

2. Has used intravenous methylprednisolone, or equivalent, within 6 weeks before Visit 1;

3. Use of concomitant medications that would potentially interfere with the actions of the IP or results of the outcome variables (Appendix D) must be stopped prior to randomization. However, concomitant use of baclofen is permitted during Screening, but subjects must stop baclofen on the day prior to randomization (Visit 3). All other prohibited concomitant medications (Appendix D) must be discontinued prior to randomization (Visit 3);

4. Has other known reproductive disorders or an identifiable history of infertility:

1. Vasoligation (surgical ligation of the vas deferens as a means of sterilization);

2. Azoospermia or severe oligospermia, asthenospermia, teratospermia, leukocytospermia, or any combination of these at baseline; or

3. Retrograde ejaculation;

5. Has had a sexually transmitted disease within the last year;

6. Has severe spasticity that makes the use of placebo medication inappropriate in the judgment of the Investigator;

7. Has had radiation to the pelvic or groin area;

8. Has a condition that affects spermatogenesis, such as recent severe genitourinary infections and prostatitis;

9. Has had previous prostate surgery or vasectomy;

10. Has been diagnosed by a urologist with any one of the following diseases:

1. Hydrocele of the tunica vaginalis;

2. Hematocele;

3. Torsion of the spermatic cord;

4. Torsion of the testicular appendage;

5. Varicocele II or more severe seminal vesiculitis;

6. Gangrene on the skin of the scrotum;

7. Cryptorchidism, small testis (12 mL, testicular volumes were determined by use of a Prader orchidometer);

8. Congenital absence of the vas deferens;

9. Tuberculosis of the epididymis; or

10. Chronic prostatitis, defined as > or equal to 3 million/mL white blood cell count in semen samples;

11. Has a history of unstable psychiatric disease, or current signs and symptoms of significant medical disorders, such as severe, progressive, or uncontrolled pulmonary, cardiac, gastrointestinal, hepatic, renal, genitourinary, hematological, endocrine, immunologic, or neurological disease;

12. Exhibits suicidality defined as active suicidal plan/intent or active suicidal thoughts in the 6 months before Screening as defined by a suicidal ideation score > or equal to 3 on the C-SSRS, (Appendix B; Has a history of suicide attempts or suicidal ideation within 1 year of Screening as determined by the C-SSRS or medical history or currently is at a serious suicidal risk in the judgment of the Investigator);

13. Has seizure disorder;

14. Has significant cognitive deficit, severe or untreated anxiety, or severe or untreated depression, which in the judgment of the Investigator, may interfere with the ability of the subject to participate in the study;

15. Has a current malignancy or history of malignancy in the last 5 years, except effectively treated basal cell skin carcinoma;

16. Has advanced or uncontrolled diabetes, human immunodeficiency virus infection, history of hepatitis C or active hepatitis B, or any other significant disease, disorder, or significant laboratory finding which, in the judgment of the Investigator, would put the subject at risk because of participation in the study, influence the result of the study, or affect the subject's ability to participate in the study;

17. Has planned elective surgery or other procedures requiring general anesthesia during the study;

18. Current chronic use of long-acting opioids or daily use of short-acting opioids for the treatment of pain;

19. Has participated in another interventional trial within 30 days of Screening;

20. Has a positive laboratory test result for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C, or controlled substances; or

21. Has a history of alcohol dependence, substance abuse, or binge drinking. The subject should avoid heavy drinking during the weeks of sperm sample collection.

Gender: Male

Minimum age: 18 Years

Maximum age: 55 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Sam Kaba, MD Study Chair Osmotica Pharmaceutical, VP - Global Clinical Development and Medical Affairs
Location
facility
Advance Medical Pain Management & Research Clinic | Miami, Florida, 33169, United States
Meridien Research | Tampa, Florida, 33604, United States
Location Countries

United States

Verification Date

August 2019

Responsible Party

Responsible party type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Arbaclofen ER Tablets

Arm group type: Experimental

Description: AERT 10 mg twice daily (BID) (20 mg/day) for 7 days, followed by AERT 15 mg BID (30 mg/day) for 7 days

Arm group label: Placebo for Arbaclofen ER Tablets

Arm group type: Placebo Comparator

Description: Matching placebo AERT 10 mg twice daily (BID) (20 mg/day) for 7 days, followed by matching placebo AERT 15 mg BID (30 mg/day) for 7 days

Patient Data No
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Other

Masking: Triple (Participant, Care Provider, Investigator)

Source: ClinicalTrials.gov