Does Kalinkathyennai enhance ovulation, compared to a placebo, in patients with Polycystic Ovary Syndrome (Soothaga Vaayu) who are undergoing treatment with clomiphene citrate (CC) or letrozole?

Study setting:

Gynecologic Clinic in Base Hospital, Balangoda. Sri Lanka.

Randomization:

The random number list and random allocation sequence will be generated by one of the colleagues of the researcher who will not be involved in the research. Sealed envelopes will be used for allocation concealment. Randomization will be done after getting all reports including D 21 Serum Progesterone level. The randomization will be stratified by age (<35 years vs >35 years) because age is strongly associated with infertility treatment success. Participants will be randomly assigned in a 1:1 ratio to the two arms such as the treatment arm and controlled arm in permuted blocks of four.

Intervention:

Bottles labelled A (Kalingathyennai) and B (Olive oil) will be prepared by the Primary Investigator. Three batches of Kalingathyennai will be prepared according to Siddha Formulary. Properly authenticated eight plant materials, viz ½ palam-17.5 grams of Cuminum cyminum (cumin seeds), Coriandrum sativum (coriander seeds), Anthum graveolens (dill seeds), Syzygium aromaticum (clove),Cinnamomum zeylanicum (cinnamon), Elettaria cardamomum (cardamom) and Curcuma longa (turmeric) will be dried under sun shade until the moisture evaporates (2-3 days). The herbs are dry when they have the texture of cornflakes and crumble when pressed. They will be powdered separately and passed through 85 sieve mesh (Strainer ladle) which will be purchased from Daraz online purchasing, Sri Lanka. An equal quantity of all the ingredients will be mixed thoroughly by hand and kept in a tightly sealed bottle. Juices will be prepared by cutting the ingredients into small pieces, pounding the mand then filtering them through a cloth. One paddi (1.3 litres) of Citrullus colcocynthis, Allium cepa (onion) & Citrus lemon (lemon) and ¼ paddi (325 ml) of Zingiber officinale (ginger juice) will be mixed with Castor oil in a mud pot and boiled. When boiling the mixture of juices, the powder indicated above will be added and mixed. When the consistency becomes thick, the oil will be taken away from the burner and allowed to cool. Oil will be filtered and transferred into clean air-tight containers and stored in a dry place for the Standardization & Randomized Control drug.

Olive oil will be purchased from Tamil Medicine Medical shops. The colour and consistency are nearly same. But smell of both oils differ since test drug contains herbal extracts. However, the primary outcome (ovulation) will not be affected while unblinding the participants although it may affect complainants, it will not be expected that the major bias on the final results. KalingathyEnnai 900 ml and 900 ml of Olive oil will be filled into 246 separate bottles (123 bottles of KalingathyEnnai and 123 bottles of Olive oil). When participants meet the VOG with the results of investigations before the menses each participant will be prescribed the standard treatment and in the sequence given the appropriate sequentially numbered sealed envelope according to her age X (<35 years) or Y (>35 years). After that, the participant will meet the Pharmacist with the prescription for standard treatment along with the sealed envelope. The pharmacist will open the envelope and issue the oil (KalingathyEnnai or Olive oil) according to A or B printed on the piece of paper within the envelope.

Participants in Group A will be given KalingathyEnnai 15ml (test medication) twice a day from Day 2 - Day 6 of menstruation. Participants in Group B will be given the placebo Olive oil 15ml twice a day from Day 2 - Day 6 of menstruation.

Kalingathyennai and Olive oil will be issued for six months since the shelf life of the oil is one year. A standard treatment will be issued for only a month, as the dose and medication will need to be adjusted after each cycle of treatment, depending on the response to treatment.

The label (A or B) will be removed by the pharmacist when he /she issues the medication. The open envelope will be resealed with its contents (trial code and label which will remove from the bottle) by the pharmacist and kept safely at the pharmacy. Therefore, the investigator and participants will be blinded to the allocation of participants to the treatment group (Kalingathyennai) or control group (Olive oil). Blinding will be only for the oils. An open labeled design will be used for the standard treatment.

Unbinding will be necessary in those that will develop any reaction (for example a skin rash), suspect to be a reaction to the trial drug, and she will be withdrawn from the study and appropriate management will be provided. If the patient is found with Insulin Resistance (IR), she will be treated with Metformin as per the clinical guidelines.

Standard therapy for all participants in the study will be clomiphene citrate 50 mg at the night, daily from day 2-6 of the cycle, for the first cycle. If ovulation is not achieved (progesterone < 20 nmol/L) in the first cycle, the dose will be doubled (Clomiphene citrate 100 mg) in the second cycle. If day 21 progesterone < 20 nmol/L on second cycle even after the dose doubled, the dose would be tripled (Clomiphene citrate 150 mg) for the 3rd cycle. If ovulation is obtained, clomiphene citrate will be prescribed at the same dose until a pregnancy is achieved or for a total of six cycles.

Participants who failed to ovulate on the maximum dose of Clomiphene citrate (150mg) will be given Letrozole 5.0 mg daily at night from Day 2 - Day 6 of menstruation. If not ovulated, the dose will be increased to Letrozole 7.5 mg at night from Day 2 - Day 6 of menstruation. The Participants who fail to ovulate on the dose of Letrozole 7.5 mg; the dose will be increased to 10mg (5mg twice a day) from Day 2 - Day 6 of menstruation for the 6th cycle.

Serial Trans Vaginal Scans (TVS) will be performed on the twelfth day of menstruation, where the number and size of the mature follicles will be evaluated. A mature follicle will be defined as a follicle with a Mean Follicular Diameter (MFD) of 18 mm and more. If at least one mature follicle has a MFD > 18 mm on the twelfth day of menstruation, a repeat TVS will be performed on Day 16 to check for the classical changes in Corpus luteum (follicular size will be reduced and honeycomb appearance), and Serum Progesterone will be done at Day 21. If progesterone level is >20 nmol/L it will be considered ovulation.

If the MFD is less than 18mm on the 12th Day, a repeat Scan will be performed at intervals of 2 days, up to Day 20, until at least one mature follicle is detected and the measurement of serum progesterone level will be adjusted according to the day at least one mature follicle is detected.

If more than 3 follicles with MFD will be 18mm or more are detected by the Day 12 scan, it will be considered ovarian hyperstimulation, and appropriate management will be implemented by a/the Consultant Obstetrician/Gynecologist and the dose of Clomiphene citrate or Letrozole will be reduced for next cycle.

Once ovulation is achieved (progesterone > 20 nmol/L), further cycles would be monitored mainly by mid-luteal phase serum progesterone levels with follicle tracking as an option. If ovulation is obtained for two consecutive cycles, standard allopathic drug, test oil and placebo oil will be prescribed for the next four months, without further monitoring. All participants will be advised about timed intercourse during the treatment cycles and treatment will be continued at the same dose until pregnancy or for up to six cycles, and the Serum Progesterone will be checked at Day 21 of 6th cycle.

The participants will be instructed to bring the oil bottle when they come to the hospital for the next visits. The balance of oil will be checked by the researcher to ensure whether the participants consumed the oil or not. If the participant fails to consume the oil (test/placebo) after the intervention, it will be considered as “did not receive the intervention”.

When participants discontinue the medicines due to the occurrence of adverse reactions or any other reasons, it will be considered as “discontinued intervention”.

When the participants fail to visit the hospital for the follow-up, it will be considered as “lost to follow up”. The investigator will be tried to communicate the lost participants by telephone calls, postcards and through the family workers and they will be requested to come back to the hospital to continue the treatment.

1. Subfertile women between 20 to 45 years with PCOS. (Subfertility defined as - Inability to conceive after 1year of regular unprotected intercourse)

2. PCOS will be diagnosed according to the International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2018. Monash University: Melbourne, Australia; Sonographic appearance of polycystic ovaries and one of the following criteria: Infrequent cycles (formerly referred to as oligomenorrhoea) or amenorrhoea; hyperandrogenism (clinical or laboratory).

3. Women who have been under any form of treatment (Allopathic or Siddha or Ayurvedic or Unani or Homeopathic or Traditional Chinese) for PCOS or subfertility within the three previous months will be recruited after three months (washout time) without taking any medication for PCOS or subfertility.

1. Women with inherited disorders such as Cushing syndrome, hyperprolactinemia, untreated hypothyroidism, congenital adrenal hyperplasia, or with an androgen-secreting ovarian/adrenal tumour and those taking a corticosteroid, antiepileptic or antipsychotic drugs.

2. Women who are not suitable for pregnancy (Uncontrolled Diabetic Mellitus, Uncontrolled Hypertension, etc) and women with Body Mass Index >30.

3. Women with tubal factor infertility and women whose partners have azoospermia.