A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial

Abstract

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active-and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (!1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean AE SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% AE 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% AE 2.9%) or placebo (0.5% AE 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. ß

Intestinal permeation enhancers for oral peptide delivery

“…The iteration of Peptelligence TM used in the ORACAL trial did not contain an acyl carnitine [192], despite their inclusion in clinical trials by Enteris with other peptides [191,193]. In preclinical testing, oral sCT absorption was increased in rat by 10-fold when LCC was included, increasing F ABS to 8% [194].…”

“…Effort has been afforded to assess the effect of regional pH on absorption of sCT, as well as several other biopharmaceutical considerations [53,82,197,199]. These studies show the relationship between intestinal pH and absorption of sCT, and while the magnitude of CA's effect on absorption of sCT is less than the combination of CA with LCC, the current NDA reflected a desire to omit PEs for regulatory reasons, whereas CA is an accepted excipient [192,200] The action of CA has been attributed to stabilisation of sCT by reduction of intestinal pH [53,198]. Fatty acid-and fatty alcohol-ethoxylates enhanced oral and rectal bioavailability of heparin and small molecules in animal models, in particular those within the series C 10 -C 16 and E 8 to E 25 [203,204], although strong enhancement is sometimes reported outside this range (e.g.…”

The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial

“…In a non-inferiority triple-arm trial, there are three rel- 31 and already used in the literature, 32 in which the study aim can be presented in a single H 0 , which simultaneously tests the non-inferiority between active treatments and their superiority against placebo, thereby decreasing the number of multiple comparisons.…”

Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage

“…It is a second line anti-resorptive treatment for osteoporosis, as well as for Paget's disease and hypercalcemia, and is marketed in injectable and nasal formats [3]. Its commercial viability for long term use in post-menopausal women has been questioned recently due to possible links to cancer, and regulatory agencies have now recommended only short term use given its relatively narrow risk-to-benefit profile [4].…”