DELAYED-START ANALYSES IN THE PHASE 3 SOLANEZUMAB EXPEDITION3 STUDY IN MILD ALZHEIMER’S DISEASE

OBJECTIVE: A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer’s disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. RESULTS: No significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer’s Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer’s Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. CONCLUSIONS: Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.

Once-Weekly Oral Alendronate 70 mg in Patients with Glucocorticoid-Induced Bone Loss: A 12-Month Randomized, Placebo-Controlled Clinical Trial

Objective.Glucocorticoid-induced osteoporosis is the most common iatrogenic form of osteoporosis. We evaluated the efficacy and safety of once-weekly bisphosphonate therapy for prevention and treatment of bone loss in patients on glucocorticoid therapy.Methods.We conducted a 12-month, multicenter, randomized, double-blind, placebo-controlled trial with 114 and 59 patients in the treatment and placebo arms, respectively. Participants were stratified according to the duration of prior oral glucocorticoid therapy at randomization. Participants received alendronate 70 mg once weekly (ALN OW) or placebo; all received supplemental daily calcium (1000 mg) and 400 IU vitamin D. Clinical evaluations were performed at baseline, 3, 6, 9, and 12 months.Results.At 12 months, there was a significant mean percentage increase from baseline in the ALN OW group for lumbar spine (2.45%), trochanter (1.27%), total hip (0.75%), and total body (1.70%) bone mineral density (BMD). Comparing ALN OW versus placebo at 12 months, a significant treatment difference for the mean percentage change from baseline was observed for lumbar spine (treatment difference of 2.92%; p ≤ 0.001), trochanter (treatment difference 1.66%; p = 0.007), and total hip (treatment difference 1.19; p = 0.008) BMD. Biochemical markers of bone remodeling also showed significant mean percentage decreases from baseline.Conclusion.Over 12 months ALN OW significantly increased lumbar spine, trochanter, total hip, and total body BMD compared with baseline among patients taking glucocorticoid therapy. A significant treatment difference versus placebo was observed at 12 months for the mean percentage change from baseline for lumbar spine, trochanter, and total hip.

Indomethacin blocks pre-partum nest building behaviour in the pig (Sus scrofa): effects on plasma prostaglandin F metabolite, oxytocin, cortisol and progesterone

In the pig, nest building occurs in the day preceding parturition (gestation=114--116 days). Nest building behaviour can be induced in pregnant, pseudopregnant and cyclic female pigs following injection of prostaglandin F2alpha. Here we investigated behaviour and endocrine changes after the administration of indomethacin, which inhibits cyclo-oxygenase enzymes and thus prostaglandin synthesis. In experiment 1, pregnant primiparous pigs (gilts) were blood sampled through jugular vein catheters every 20 min from 1000 h on day 113 of pregnancy and behaviour was recorded until birth. Two hours after pre-partum nest building began, animals received 4 mg/kg indomethacin (n=7) or control vehicle (n=8) intramuscularly. Indomethacin-treated animals showed less nest building than controls between 1 and 5 h after injection (P<0.05), during which time they were mostly inactive and lay down for longer than controls. From 5 h before birth until birth there was no significant treatment difference in nest building behaviour. There was a tendency for the start of birth to be delayed in indomethacin-treated animals. Plasma 13,14-dihydro-15-keto-prostaglandin F2 alpha (a major metabolite of prostaglandin F2 alpha) rose during pre-injection nest building and then fell following indomethacin treatment, but was not significantly different between groups when behaviour differed. Plasma oxytocin, cortisol and progesterone were not significantly affected by treatment. In experiment 2, indomethacin-treated non-pregnant gilts (n=7) did not show any changes in activity or posture compared with vehicle-treated controls (n=6) between 90 and 150 min after treatment. These results suggested that indomethacin treatment reversibly and specifically inhibits porcine pre-partum nest building by a mechanism that may involve endogenous prostaglandin F2 alpha synthesis inhibition but is independent of circulating oxytocin, cortisol and progesterone concentrations.

EFFECT OF LOW DIETARY ZINC DURING LATE GESTATION AND EARLY LACTATION ON THE SOW AND NEONATAL PIGLETS

Twelve pregnant sows were fed semi-purified diets containing either 13 or 63 mg/kg zinc (Zn). The animals were fed the diets during the last 4 wk of pregnancy (2 kg/day) and the two first weeks of lactation (ad libitum). Reduced level of dietary Zn did not affect (P > 0.05) weight changes of sows and no difference (P > 0.05) in food intake occurred during the ad libitum phase of the experiment. Low Zn sows showed lower plasma Zn at 100 (125 vs. 157 g/dL) and 113 (93 vs. 127 g/dL) days of gestation and at 7 (65 vs. 133 g/dL)) and 14 (59 vs. 99 g/dL) days of lactation. The differences were significant (P < 0.01) only during lactation. Copper (Cu), iron (Fe) and ammonia (NH3) concentrations in plasma and alkaline phosphatase activity (APA) of plasma were not affected by treatment. Parturition lasted 2.08 h in control and 4.54 h in low Zn sows (P < 0.1). Zinc, Cu and protein content of colostrum and milk were similar between groups. Low dietary Zn had no effect on litter size, birth weight, number of stillbirths and mortality up to 2 wk of age. Liveweight at 7 days was significantly higher in piglets nursed by low Zn dams but at 14 days of age no significant treatment difference was found. Zinc, Cu Fe, NH3 concentrations in plasma and APA in plasma of piglets were not significantly different at birth or at 7 days of age. At 14 days of age only plasma Zn was significantly reduced (P < 0.05). Low supply of Zn to dams had no effect on the performance of piglets during neonatal life. Key words: Zinc, sows, pregnancy, lactation, piglets

Effect of environmental temperature on suckling pigs and a study of the milk yield of the sow

1. A study was made of the performance of eight litters of pigs housed under two widely different levels of ambient temperature during the suckling period and under uniform conditions from weaning to 200 lb. live weight.2. There was no significant treatment difference in the amount of milk suckled, but the pigs exposed to the lower temperature consumed more solid food before weaning.3. Up to weaning those kept at the higher temperature were the more efficient converters of milk and solid food into live weight.4. There was a highly significant correlation between milk suckled and live-weight gain.5. Probably through excessive handling, the pigs were under weight at weaning, but the postweaning performance appeared to be unaffected by the pre-weaning treatment.6. The average milk yield of six sows from the 3rd to the 56th day of lactation was 275 kg. 605 lb.) (variations 202–347 kg. (445–764 lb.)). Yields have been compared with others published.7. After allowing for maintenance requirements and weight gain or loss it is estimated that the sows required 412 Calories of net energy to produce 1 lb. of milk.