Overview

This Randomized Clinical Trial entitled Safety and Efficacy of a Peripherally Restricted Selective Kappa Agonist for Moderate to Severe Menopausal Symptoms in Midlife Women is a Phase 2a randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of asimadoline TP0052 for the treatment of moderate to severe menopausal vasomotor symptoms (VMS). The design includes: 2 weeks of daily recording of VMS prior to drug treatment; 8 weeks of double-blind treatment with the peripherally restricted kappa agonist (PRKA), asimadoline TP0052, or placebo; and a safety telephone follow-up post-treatment; after the initial 8-week double-blinded follow-up, all patients undergo treatment with Asimadoline in an open label format for 4 weeks.

Eligibility

Inclusion Criteria

• Females aged 40-62 years.
• Untreated patients (either newly diagnosed with VMS or those with a history of VMS but have not been taking drugs that could have an effect on VMS (e.g., SSRIs, SNRIs, gabapentin, pregabalin, clonidine).
• Menopausal OR late perimenopausal according to the following criteria:

Criteria for Menopause:

• Women who have had a bi-lateral oophorectomy (> 6 weeks prior); OR
• Women with a uterus who have had no vaginal bleeding the past 12 months; OR
• Women without a uterus (or women with a uterus who have either a levonorgestrel intrauterine device [LNG IUD] or who have had an endometrial ablation) and who still have one or both ovaries, with follicle stimulating hormone (FSH) level > 40 mIU/mL and estradiol ≤ 50 pg/mL (on at least one of two blood draws two weeks apart);

Criteria for Late Perimenopause:

• Women with a uterus who have had consecutive intervals of amenorrhea of at least 60 days for three or more cycles (i.e., three consecutive episodes of vaginal bleeding separated by 60 or more days between vaginal bleeding episodes).

  • At least 40 moderate to severe VMS per week for each of the 2 screening weeks, as reported on daily VMS diaries.

• Including at least 6 moderate to severe VMS per day on 4 or more days in each of the 2 screening weeks.
• VMS frequency in week 2 cannot drop by more than 50% from the average weekly level reported during week 1.
  • In general good health as determined by medical history, blood pressure, and heart rate.
  • Signed informed consent.

Exclusion Criteria

• • Use of hormone therapy or hormonal contraceptives (with the exception of the LNG IUD) during the 8 weeks before Screening Visit 1. Use of low-dose vaginal estrogen therapies is allowed, with the exception of vaginal creams used >3 times a week.
• Use of non-hormonal medications that can influence VMS during the 4 weeks before Screening Visit 1, including selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, and clonidine.
• Use of marijuana or cannabis-derived products (including THC or CBD in any form other than topical, including smoked, vaporized, or edible) that can affect central thermoregulatory processes, mood and perception of VMS, and potentially have pharmacodynamic interactions with the asimadoline during the 4 weeks before Screening Visit 1 as determined by interview and urine drug test.
• Use of supplements or herbal therapies that can affect VMS including black cohosh, red clover, dong quai, evening primrose oil, maca, ginseng, chasteberry, milk thistle, and phytoestrogens during the 4 weeks before Screening Visit 1.
• Any current severe or unstable medical illness, including the following:
  • Hypertension of stage 2 or greater (systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90)
  • Resting heart rate >100.
  • Current cancer diagnosis, except non-melanoma skin cancer, or any findings suggestive of or indicating breast malignancy.
  • Current abnormal Pap smear, breast exam, or mammogram.
  • Coronary artery disease, or cerebrovascular disease.
  • Moderate to severe substance use disorder in the previous 12 months; suicide attempt in the previous 36 months, any major depressive episode within the previous 12 months, or lifetime diagnosis of psychosis or bipolar disorder.
• Pregnancy, intending pregnancy, breast feeding.
• Current participation in another drug trial or intervention study.
• Inability or unwillingness to complete the study procedures.

Trial-Specific Exclusion Criteria:

• Known hypersensitivity to asimadoline TP0052.
• Chronic liver or renal disease, or uncontrolled seizure disorder.
• Use of medications or supplements that act as an inhibitor of P-glycoprotein or as a P-glycoprotein substrate during the 4 weeks prior to Screening Visit 1, including cyclosporine, non-topical ketoconazole, verapamil, digoxin, colchicine, sitagliptin).
• Blood test results indicating:
  • Liver function tests: AST ≥2 times upper limit of normal; ALT ≥2 times upper limit of normal; total bilirubin ≥ 1.5 times upper limit of normal
  • Kidney function test: estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²
  • Blood count: hematocrit <30%.