Rapamycin for Perimenopause

(Rapamycin Trial)

Overseen By Stephanie Morgan

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: Columbia University

Disqualifiers: Irregular cycles, Severe ovarian deficiency, Kidney or liver disease, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a low dose of rapamycin (also known as Sirolimus) can slow ovarian aging in women. Rapamycin has shown promise in animal studies for slowing aging-related changes. Participants will receive either rapamycin or a placebo for 12 weeks to evaluate its effects. Women aged 35-45, experiencing regular periods, and having difficulty conceiving due to diminished ovarian reserve may be suitable for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in fertility treatment.

Do I need to stop my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more information.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have shown that rapamycin is quite safe in low doses. Research indicates that using small amounts of rapamycin for 48 weeks did not cause major safety problems in healthy adults, suggesting the drug is generally well-tolerated. Another study found that rapamycin might safely protect ovarian health, although long-term use could have some negative effects. The treatment already has approval for other uses, further supporting its safety. These findings can reassure prospective trial participants about the safety of rapamycin in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for perimenopause, which often include hormone replacement therapy, Rapamycin offers a unique approach by targeting cellular aging processes. Rapamycin works through a mechanism of action that inhibits the mTOR pathway, potentially influencing aging and longevity at the cellular level. Researchers are excited about Rapamycin because it could address some of the underlying biological changes associated with perimenopause, rather than just alleviating symptoms. This could open up new avenues for managing perimenopause with potentially fewer hormonal side effects.

What evidence suggests that rapamycin might be an effective treatment for perimenopause?

Research shows that rapamycin, which participants in this trial may receive, might help delay ovarian aging. Animal studies have found that rapamycin can slow or even reverse some aging effects in the ovaries. Specifically, earlier reports indicated that rapamycin reduced ovarian aging by about 20% without causing side effects. This suggests it could potentially extend a woman's fertility by up to five years. These promising results make rapamycin an exciting option to explore for managing perimenopause. ^{1 2 6 7 8}

Who Is on the Research Team?

Samuel Z. Williams, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for women aged 38-45 in the early stages of menopause, who have struggled with fertility due to diminished ovarian reserve. They should still have regular menstrual cycles and specific hormone levels within a set range. It's not suitable for those outside this age group or stage of menopause.

Inclusion Criteria

In the menopausal transition stage -3a

Have regular menstrual periods (with less than 7 days of variability)

Early follicular phase follicle stimulating hormone (FSH) levels ] < 20 mIU/mL

Exclusion Criteria

Severe ovarian deficiency, or with no evidence of remaining follicles

I have kidney or liver disease.

My menstrual cycles are irregular.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 5mg/week of rapamycin or placebo orally for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including measurement of ovarian reserve and hormone levels

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Rapamycin

Trial Overview The study tests if low-dose Rapamycin can delay the process of ovarian aging compared to a placebo. Participants won't know which one they're getting as it's a double-blind study, meaning neither the participants nor the researchers know who receives Rapamycin or placebo until after the results are collected.

How Is the Trial Designed?

Group I: Rapamycin Experimental Treatment 1 Intervention

Participants randomized to the treatment arm will receive 5mg/week of rapamycin orally, for 12 weeks (3 months).

Group II: Placebo Placebo Group 1 Intervention

Participants randomized to the placebo arm will receive placebo orally, for 12 weeks (3 months).

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Published Research Related to This Trial

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

A 14-day study of sirolimus in renal transplant patients showed that it can be safely combined with cyclosporine and corticosteroids, as it did not significantly affect kidney function or blood pressure.

While sirolimus caused a reversible decrease in platelet and white blood cell counts and increased cholesterol levels, these side effects were manageable and distinct from the nephrotoxic effects of cyclosporine, suggesting a potential for effective immunosuppression without added toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Murgia, MG., Jordan, S., Kahan, BD.[2019]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

Blocking the mTOR pathway with inhibitors like everolimus can effectively preserve ovarian function and fertility in premenopausal women undergoing chemotherapy, as demonstrated in a mouse model of chemotherapy-induced gonadotoxicity.

The study showed that mTOR inhibition maintained primordial follicle counts and serum anti-Mullerian hormone levels, leading to normal fertility outcomes, suggesting a promising approach for fertility preservation during cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy. Goldman, KN., Chenette, D., Arju, R., et al.[2018]

Caloric restriction (CR) and rapamycin both significantly increased the number of primordial follicles in female mice, suggesting they can help preserve ovarian reserve and potentially delay menopause.

While CR improved insulin sensitivity and reduced body weight, rapamycin did not affect body weight and induced insulin resistance, indicating that these two interventions have different metabolic effects despite similar benefits on ovarian reserve.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of caloric restriction and rapamycin on ovarian aging in mice. Garcia, DN., Saccon, TD., Pradiee, J., et al.[2020]

In a study using 8-week old female mice, rapamycin was found to significantly protect primordial follicles from depletion caused by the chemotherapy drug cyclophosphamide, indicating its potential as a protective treatment for ovarian function during chemotherapy.

The protective effect of rapamycin is linked to its ability to modulate the PI3K/Akt/mTOR signaling pathway, preventing premature activation of primordial follicles and maintaining normal levels of serum anti-Müllerian hormone (AMH) compared to those treated with cyclophosphamide alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. Zhou, L., Xie, Y., Li, S., et al.[2021]

In a phase III study, everolimus significantly improved progression-free survival in patients with metastatic renal cell carcinoma, showing a median of 4.9 months compared to 1.9 months for placebo, with a strong hazard ratio of 0.33 (P < 0.001).

The treatment had a low discontinuation rate due to adverse events (10%) and maintained health-related quality of life, indicating that everolimus is both effective and well-tolerated in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience and critical evaluation of the role of everolimus in advanced renal cell carcinoma. Sun, M., Abdollah, F., Schmitges, J., et al.[2021]

Nanomolar concentrations of mTOR inhibitors like rapamycin, everolimus, and temsirolimus reduce the proliferation of ovarian granulosa cells and inhibit follicle growth, indicating a potential safety concern at higher doses.

In contrast, picomolar concentrations of rapamycin can accelerate follicle growth, but this effect is dependent on the presence of estradiol, suggesting a complex mechanism of action that could be harnessed for therapeutic purposes in ovarian follicle development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross talk between estradiol and mTOR kinase in the regulation of ovarian granulosa proliferation. Yu, J., Thomson, TC., Johnson, J.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3895422/

Rapamycin prolongs female reproductive lifespan - PMC In summary, our data indicate that rapamycin treatment has beneficial effects on the reserve of ovarian follicle pool and female reproductive ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05836025

NCT05836025 | Effect of Rapamycin in Ovarian Aging A prospective, randomized, double-blind, placebo-controlled pilot study assessing the ability of low-dose rapamycin to delay ovarian aging in women.

3. medicalnewstoday.com medicalnewstoday.com/articles/common-drug-could-extend-womens-fertility-by-as-much-as-5-years

Rapamycin may help extend women's fertility by 5 years “The findings from the pilot study are promising, suggesting that rapamycin could decrease ovarian ageing by 20% without side effects. This is ...

4. gethealthspan.com gethealthspan.com/science/article/rapamycin-for-menopause?srsltid=AfmBOorVmvXEV75hCHMe_ACI2LXOgx_ySOciJwq79359PNOWWuFh6rvX

Exploring Rapamycin's Potential Role in Managing ... Rapamycin shows the potential to extend the reproductive lifespan and delay menopausal changes observed in animal studies. It could improve ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11736300/

Impact of Age, Menopause, and Sirolimus on Spontaneous ... The major findings of our analysis are that in patients with LAM, increasing age and menopausal status are associated with a reduced risk of development of SP, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12074816/

Influence of rapamycin on safety and healthspan metrics ... Conclusions: Low-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with ...

7. theguardian.com theguardian.com/society/article/2024/jul/22/drug-women-fertility-study-rapamycin

'Dream come true': study suggests drug could extend ... Co-lead says rapamycin can be repurposed to slow ovaries from ageing and is safe for younger women.

8. withpower.com withpower.com/trial/phase-2-perimenopausal-3-2023-8e65a

Rapamycin for Perimenopause · Info for Participants Rapamycin has shown potential for preserving ovarian health, but using it for an extended period can have negative effects. The goal is to extend the time women ...