Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT05114980 |
Other study ID # |
IRB-3000008285 |
Secondary ID |
|
Status |
Recruiting |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
July 2024 |
Est. completion date |
January 2027 |
Study information
Verified date |
June 2023 |
Source |
University of Alabama at Birmingham |
Contact |
Polina Zmijewski, MD |
Phone |
205-934-3333 |
Email |
pzmijewski[@]uabmc.edu |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Options for treatment of severe, refractory hypocalcemia are limited for the thousands of
patients in the United States who suffer from hypoparathyroidism. Parathyroid
allotransplantation is an emerging treatment that provides hope for these individuals.
Currently, this therapy has only been successfully provided by a few centers in the world. In
the UAB PATH trial, we propose to become one of the few centers worldwide to successfully
achieve parathyroid allotransplantation in transplant-naïve patients.
Description:
Hypoparathyroidism (HypoPT) is a clinical condition characterized by hypocalcemia and low
parathyroid hormone levels (PTH). HypoPT is most often the result from previous neck surgery
such as thyroidectomy, parathyroidectomy and cervical dissection. It can also result in
autoimmune damage to parathyroid glands or genetic disorders. Based on analysis of a large
health plan claims database, the estimated prevalence of hypoparathyroidism in the United
States is 77,000 cases.[1] Most patients with symptoms present with neuromuscular
irritability such as muscle spam, paresthesia, laryngospasm and seizure. Long-term
complications from HypoPT include renal impairment, cataracts and basal ganglia
calcification.[2] A health-related quality of life (QoL) survey across 13 countries showed
that 84% of patients reports impacts for ability to exercise (84%), sleep (78%), ability to
work (75%) and family relationships (63%).[3] Hypoparathyroidism is typically managed with
calcium, vitamin D and at times, thiazide diuretics. Acute hypocalcemia or severe symptomatic
hypocalcemia may require intravenous calcium administration. Recombinant Human(rh) PTH (1-84)
was approved by the U.S Food and Drug Administration (FDA) for the management of
hypoparathyroidism in 2015.[4] Studies showed that rhPTH (1-84) can reduce the need for
supplemental calcium and active vitamin D and improve patients' QoL. However, rhPTH (1-84) is
only available through a registry known as Risk Evaluation and Mitigation Strategies (REMS)
due to its potential risk for development of osteosarcoma, and patients are not frequently
able to remain on this medication for the long-term.[5] Also not every patient is responsive
to rhPTH.[6] Thus, an alternative, less costly and effective treatment is required to
physiologically restore parathyroid function.
Parathyroid gland transplant (PGTx) has been explored for the past 60 years. Groth et al.
reported the first case of parathyroid allotransplant in 1973. A 46 year-old male who
underwent subtotal parathyroidectomy due to secondary hyperparathyroidism in 1970 developed
hypoparathyroidism after cadaveric renal transplantation. Four separate pieces of homologous
hyperplastic parathyroid tissue were implanted into his pectoralis muscle 52 days after renal
transplantation in 1971. He was able to stop all supplementation 2 months after PGTx and his
serum calcium and phosphorus had been within normal limits in the next 12 months.[7] Since
then, several successful cases of PGTx were performed on renal transplant recipients across
the world. Of all these cases, patients has already been on immunosuppressants. [8-13] A
online survey regarding patients' view about parathyroid transplantation was conducted in the
United Kingdom in 2018. Two thirds of patient interested in further development of
parathyroid transplantation. The main concern was the possible need for immunosuppressive
therapy.[14] Several case reports attempted to use cell culture techniques [15] and
microencapsulation[16] to reduce immunogenicity to avoid immunosuppressants. However, the
allograft survival rate was low comparing to patients who take immunosuppressants.
Case Reports of PGTx in non-transplant recipients who received immunosuppressants after
transplant were reported first in Mexico in 2015 and in Germany in 2016. Hermosillo-Sandoval
et al. in Mexico reported in their case series that 5 patients with iatrogenic
hypoparathyroidism received PGTx from donors of primary hyperparathyroidism. In the 2-year
follow up, all patients reduced calcium supplement from an average of 8.4g calcium carbonate
per day to an average of 6g/day with no immunosuppression related complications reported.
Sestamibi scintigraphy and Doppler ultrasound showed 4 patients had radiopharmaceutical
uptake with blood flow. [17] Agha et al. in Germany reported a case of a 32-year old female
with iatrogenic refractory hypoparathyroidism receiving two normal parathyroid glands from
her brother. The recipient stopped PTH (1-1-84) after transplantation and PTH levels remained
within the normal range for three years after transplantation. Neither the donor nor
recipient experienced any surgical complications.[6]
This is a non-randomized pilot study that will evaluate feasibility of parathyroid
allotransplantation using deceased donors to treat medically refractory hypoparathyroidism in
transplant-naïve patients. Patients with permanent refractory hypoparathyroidism will be
referred to parathyroid team via comprehensive transplant institute (CTI), endocrine surgery
office, faxed referral form, MD to MD personal relationship and access center. Based upon
review of referral, the parathyroid team will decide if patient is a candidate for
evaluation. If patient meets the selection criteria, the parathyroid team will begin the
telephone screening. Parathyroid team will order the required evaluation labs (Vitamin D25 OH
level, comprehensive metabolic panel (CMP), complete blood count (CBC) with differential
count, parathyroid hormone (PTH) level, human leukocyte antigen (HLA) testing and ABO x 2).
The parathyroid team will schedule virtual consults for surgery, nutrition, pharmacy, social
work, transplant financial coordinator, and transplant education. In-person clinic visits
will occur at MD discretion. Evaluation patients will be presented by the Transplant MD and
discussed by the multidisciplinary team to determine suitability for transplant. If candidate
is suitable for transplant, proceed with listing process and expectations.
Legacy of Hope (LOH), the Organ Procurement Organization, will notify parathyroid surgeon of
any offers. Once accepted, the parathyroid surgeon will contact the kidney Pre-Transplant
Coordinator (PTC) on call regarding organ offer and crossmatch on potential transplant
candidates. If suitable for organ offer, the parathyroid team will contact patient and begin
the admission process. The endocrine procurement team will prepare parathyroid glands for
explant using standard surgical techniques. Biopsies of each candidate parathyroid will be
obtained and sent for frozen section. The Pathologist on-call will evaluate the procured
specimen to confirm the tissue as parathyroid glands. All glands will be combined in one
specimen cup in perfusion solution. The specimen will be kept on iced saline for transport.
The specimen will transported to UAB using standardized protocols for transplant organ tissue
handling.
The recipient will receive 250mg methylprednisolone intravenous in the operating room for
induction immunosuppression. The parathyroid transplantation will be performed under local
anesthesia using well established technique of implanting parathyroid tissue in the
non-dominant brachioradialis muscle. The recipient will be transferred back to the ward after
the procedure for observation.
Patients will start on postoperative immunosuppression and postoperative prophylaxis based on
UAB protocol. The patient is discharged on the same day as the procedure. In the pre-graft
function phase, the patient will receive a daily phone check-in with labs every other day
including CBC, basic metabolic panel (BMP), PTH, ionized calcium and tacrolimus level, and
clinic visits twice weekly with surgeon-performed ultrasound of graft. In the post-graft
function phase, patients will receive weekly labs for 3 months including CBC, CMP, PTH,
tacrolimus and weekly clinic visit for 3 months. Afterwards, patient will start monthly
clinic visits for 1 year. Patients will also obtain donor-specific antibody (DSA) testing at
1, 3, 6 months after transplant and every 3 months thereafter.