Pharmacokinetic and PHarmacodynamic Analysis and Evaluation of Teriparatide (PTH 1-34) Between Sexes
Condition: Stress Fracture
MeSH terms: Fractures, Stress
Study type: Interventional
Phase: Phase 3

Summary: 
      To test for a difference in the pharmacokinetics (PK) and pharmacodynamics (PD) of
      teriparatide (PTH 1-34), between healthy male and female volunteers matched to military
      recruits in training.
    

Detailed description: 
      Teriparatide, first licensed for fracture prevention in osteoporosis in 2003, is a human
      recombinant preparation of parathyroid hormone (PTH) 1-34. The licensed dose is a 20 µg
      sub-cutaneous (S/C) injection delivered once daily using a pre-filled pen. Published
      pharmacokinetic (PK) and pharmacodynamic (PD) data focus on administration in adult female
      pre-menopausal women. Eli Lilly did not publish their original 'First in Human' data,
      therefore there is a lack of available data in men. The patent on the Eli Lilly formulation
      expired in August 2019 and three teriparatide biosimilars have been released onto the UK
      market. Gedeon Richter and Thornton and Ross presented data in osteoporotic patients to the
      MHRA to license their products as biosimilars. Teriparatide has also been investigated in the
      treatment of stress fractures, but there are no published data comparing the PKs and PDs of
      these drugs in a population equivalent to individuals undergoing military training (i.e.
      young healthy men and women).

      Existing data to support the equivalence of teriparatide between sexes is limited. Citrate
      and calcium infusions have been used to characterise the impact of sex differences on PTH
      dynamics in twelve women with mean age ± SD of 26.4 ± 1.6 years and 12 men with mean age of
      26.6 ± 1.3 years. They reported no between sex differences in serum PTH concentrations. It
      has also been reported that 2-weeks of intermittent PTH administration in mice was anabolic
      for cortical bone, with a greater effect observed in male compared with female animals. No
      studies have investigated between sex PK or PD differences or efficacy of teriparatide
      injection in humans. By examining this, the present study will help to further our
      understanding of how teriparatide can be used in men and women.

      A review considering a number of trials supported the use of PTH in its licensed indications
      and demonstrated the efficacy of this drug in both male and female subjects. The evidence
      base cited in this review is primarily from post-menopausal women in line with the licensed
      indication.

      This study compliments the RETURN trial which is investigating the efficacy of teriparatide
      for accelerating stress fracture healing in Army infantry recruits (EudraCT: 2018-002130-20).
      The study is based at the Infantry Training Centre (ITC), which currently predominantly
      trains men, hence men will form the majority of the RETURN study participants. Opening front
      line roles to women comes with a well-documented risk of musculoskeletal injury due to the
      nature of infantry training (HQ Army, 2016). If the results of the RETURN trial are to be
      extrapolated to women and inform Defence treatment policy for stress fractures, the between
      sex differences in PK and PD in a population matched to individuals in military training must
      be established. This study is required if the results of RETURN are to be extrapolated to a
      female population undergoing military training.

      The Gedeon Richter preparation, 'Terossa' will be used in this study as this is the
      preparation that is being used in the RETURN study. This will control for inter-brand
      variation.

      Nephrogenous cyclic Adenosine Mono Phosphate is a measurement of PTH 1-34 activity at the
      kidney and can therefore be used to estimate the early biological effects of PTH 1-34 in
      humans.

      The research questions are;

        1. Is there a difference in the PK or PD profile of teriparatide subcutaneous injection
           between men and women?

        2. Are the PK and PD measurements reliable and reproducible? The cohort for investigation
           is young healthy (free from immune, cardiovascular or metabolic diseases) men and women,
           military or physically trained civilians, free from illness, and matched to a military
           population in training, based on age, body mass index (BMI) and absence of medical
           conditions that would be a bar to entry to the Army (Can I Join The Army | Find Out if
           You Are Eligible | British Army - British Army Jobs (mod.uk) [Accessed 16/01/2021]).

      The intervention involves a single dose of teriparatide administered on 2 occasions.

      Participants will be closely monitored for 12 hours, plus a further 12 hours urine collection
      followed by a 24-hour washout period.
    

Intervention name(s): Teriparatide
Intervention type(s): Drug
Intervention description(s): PTH(1-34) cartridge and pen device
Intervention MeSH terms: Teriparatide
Intervention model: Single Group Assignment
Intervention model description: This is an open-label, parallel, clinical trial in two separate groups, men and women.
Masking: None (Open Label)
Primary purpose: Other